A mechanism converting psychosocial stress into mononuclear cell activation
Open accessAbstract
Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor κB (NF-κB). Therefore, NF-κB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-κB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-κB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-κB-controlled β-globin transgene were stressed by immobilization. Immobilization resulted in increased β-globin expression, which could be reduced in the presence of the α1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-κB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-κB and NF-κB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by α 1 - and β-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-κB in vitro and in vivo . Activation of NF-κB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.
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- Findingown data
After mental stress induction at 60 min, NF-kB-binding activity had almost completely returned to baseline (166%; P=0.073).
“After mental stress induction (60 min), NF-B-binding activity had almost completely returned to baseline (166%; P ϭ 0.073) (Fig. 1b).”
Quote in the paperSubstantial claim - Findingown data
The TSST significantly increases ACTH and cortisol plasma levels after stress.
“ACTH and cortisol plasma levels served as markers of the endocrine stress response, demonstrating the expected significant increases in ACTH and cortisol after stress (P Ͻ 0.0001; Fig. 1a Upper).”
Quote in the paperSubstantial claim - Findingown data
Only weak signals for beta-globin mRNA were detected in control mice.
“Only weak signals for -globin mRNA could be detected in control mice (Fig. 2a Upper, lanes 1-3).”
Quote in the paperNot a substantial claim - Findingown data
The TSST significantly increases AD and NA levels already 1 min after stress induction.
“The TSST further significantly increased AD and NA levels already 1 min after stress induction.(Fig. 1a Lower).”
Quote in the paperSubstantial claim - Findingown data
The TSST induces NF-kB-binding activity in PBMC from 100% to 341% at 10 min after stress induction.
“The TSST-mediated induction of NF-B-binding activity from 100% to 341% (P ϭ 0.0089) observed in PBMC 10 min after stress induction (Fig. 1b)”
Quote in the paperSubstantial claim
- Findingown data
In four randomly selected spectators watching the TSST, no up-regulation of NF-kB was observed during the assay period.
“In none of the spectators, up-regulation of NF-B could be observed during the assay period (Fig. 1c).”
Quote in the paperSubstantial claim - Findingown data
Two subjects without a stress-dependent increase in catecholamines, ACTH, and cortisol did not induce NF-kB-binding activity.
“Two subjects, characterized by the absence of a stress-dependent increase in catecholamines, ACTH, and cortisol, did not induce NF-Bbinding activity,”
Quote in the paperSubstantial claim - Findingown data
No changes in OCT-1-binding activity were detected in the TSST experiment.
“No changes in OCT-1-binding activity were detected (Fig. 1d Right), as shown for one representative subject (Fig. 1d Left).”
Quote in the paperSubstantial claim - Findingown data
The composition of NF-kB subunits contributing to NF-kB-binding activity did not change during the recovery period.
“Although the intensity of NF-B-binding activity decreased in the recovery period, the composition of the NF-B subunits contributing to the NF-Bbinding activity did not change (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
Metoprolol and butoxamine also reduced the NA-dependent NF-kB response in THP-1 cells.
“The  1 -antagonist metoprolol (100 nM) and the  2 -antagonist butoxamine (25 nM) also reduced the NA-dependent NF-B response (Fig. 4a, lanes 5 and 6).”
Quote in the paperSubstantial claim - Findingown data
Yohimbine had no effect on NA-dependent NF-kB response.
“The ␣ 2 -antagonist yohimbine (10 nM) had no effect (Fig. 4a, lane 4)”
Quote in the paperSubstantial claim - Findingown data
The NF-kB subunits contributing to NA-induced NF-kB binding in THP-1 cells were p50, p65, cRel, and Rel B.
“The NF-B subunits contributing to the NA-induced NF-B binding in THP-1 cells were identified as p50, p65, cRel, and Rel B (Fig. 3d).”
Quote in the paperSubstantial claim - Findingown data
Physiological concentrations of NA were sufficient to result in a significant increase in NF-kB-binding activity in THP-1 cells in a dose- and time-dependent manner.
“In contrast, physiological concentrations of NA were sufficient to result in a significant increase in NF-B-binding activity in a dose-(Fig.3b) and timedependent manner (Fig. 3c).”
Quote in the paperSubstantial claim - Findingown data
Cholera toxin increased NA-induced NF-kB activation.
“preincubation with cholera toxin (5 g͞ml), stimulating G s , increased NA-induced NF-B activation (Fig. 4b”
Quote in the paperSubstantial claim - Findingown data
NA-dependent activation of NF-kB was inhibited in the presence of PI3-kinase, Ras, Raf, and MAPK inhibitors and by the antioxidant thioctic acid.
“Consistently, NA-dependent activation of NF-B was inhibited in the presence of PI3-kinase, Ras, Raf, and MAPK inhibitors and by the antioxidant thioctic acid as summarized in Fig. 4d.”
Quote in the paperSubstantial claim - Findingown data
Blood samples of immobilized mice demonstrated a strong increase in beta-globin mRNA.
“In contrast, blood samples of immobilized mice demonstrated a strong increase in -globin mRNA (Fig. 2a Upper, lanes 4-6).”
Quote in the paperSubstantial claim - Findingown data
The concentration of AD needed to significantly induce NF-kB-binding activity in THP-1 cells was 100-fold higher than the concentration determined in volunteers undergoing the TSST.
“When cultured THP-1 cells were stimulated with 10 fM to 1 M AD (Fig. 3a) or NA (Fig. 3b), the concentration of AD needed to significantly induce NF-B-binding activity (Fig. 3a) was 100-fold higher than the concentration determined in volunteers undergoing the TSST.”
Quote in the paperSubstantial claim - Findingown data
Thioctic acid reduced NA-dependent NF-kB activation by 23% in THP-1 cells.
“Thioctic acid (2 mM), known to inhibit reactive oxygen species-mediated NF-B activation (38), reduced NA-dependent NF-B activation by 23% (Fig. 4b, lane 3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] 38. Packer, L. (1998) Drug Metab. Rev. 30, 245-275.
Not checked in the free run.
- Findingown data
NA induced a dose-dependent increase in NF-kB-regulated IL-6 transcription in THP-1 cells.
“RT-PCR demonstrated that the observed increase in NF-B-binding activity was functionally significant because NA induced a dose-dependent increase in NF-B regulated IL-6 transcription in these cells (Fig. 3e).”
Quote in the paperSubstantial claim - Findingown data
Preincubation with prazosin resulted in a significant decrease in NA-dependent NF-kB-binding activity in THP-1 cells.
“Consistent with the observation in immobilized mice (Fig. 2), preincubation with the ␣ 1 -antagonist prazosin (1 nM) resulted in a significant decrease in NF-B-binding activity (Fig. 4a, lane 3).”
Quote in the paperSubstantial claim - Findingown data
Stress-induced beta-globin transcription was reduced in immobilized mice pretreated with prazosin.
“Stress-induced -globin transcription was reduced in this group of mice (Fig. 2a Upper, lanes 7-9).”
Quote in the paperSubstantial claim - Findingown data
Noradrenaline-induced NF-κB activation was reduced by α1- and β-adrenergic inhibitors.
“Induction was reduced by ␣1and -adrenergic inhibitors.”
Quote in the paperSubstantial claim - Findingown data
Adrenaline concentrations achieved in volunteers undergoing the TSST are much too low compared to the concentration of adrenaline required for induction of NF-κB activation in vitro.
“although the AD concentrations achieved in volunteers undergoing the TSST are much to low compared to the concentration of AD required for induction of NF-B activation in vitro (Figs.1a and 3a).”
Quote in the paperSubstantial claim - Findingown data
Adrenaline release correlates with the extent of NF-κB activation.
“AD release correlates with the extent of NF-B activation (data not shown)”
Quote in the paperSubstantial claim - Premisecitation§ A mechanism converting psychosocial stress into mononuclear cell activation
Changes in mononuclear properties are consistent with activation of the redox-sensitive transcription factor NF-kB.
“These changes in mononuclear properties are consistent with the activation of the redox-sensitive transcription factor nuclear factor B (NF-B) (24)(25)(26)(27)(28)(29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (24)(25)(26)(27)(28)(29)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The rapid NF-kB activation observed in volunteers undergoing the TSST was caused by psychosocial stress.
“This suggests that the rapid NF-B activation observed in volunteers undergoing the TSST was indeed caused by psychosocial stress.”
Quote in the paperSubstantial claim - Interpretationcitation§ A mechanism converting psychosocial stress into mononuclear cell activation
There is a strong causal relationship between chronic stress and the development of atherosclerosis.
“suggesting a strong causal relationship between chronic stress and the development of atherosclerosis (1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] 1. Rozanski, A., Blumenthal, J. A. & Kaplan, J. (2000) Circulation 99, 2192-2217.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
NF-kB activation depends on the acute response to psychosocial stress.
“indicating that NF-B activation depends on the acute response to psychosocial stress.”
Quote in the paperSubstantial claim - Premisecitation§ A mechanism converting psychosocial stress into mononuclear cell activation
Animal studies describe stress-increased NF-kB activation and subsequent NF-kB-dependent gene expression in the brain cortex of rats exposed to immobilization stress.
“Indirect evidence for a role of NF-B in mediating cellular effects in response to psychosocial stress comes from animal studies describing stress-increased NF-B activation and subsequent NF-B-dependent gene expression in the brain cortex of rats exposed to immobilization stress (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] 30. Madrigal, J. L., Hurtado, O., Moro, M. A., Lizasoain, I., Lorenzo, P., Castrilli, A., Bosca, L. & Leza, J. C. (2002) Neuropsychopharmacology 26, 155-163.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Ras interacts with the serine/threonine kinase Raf, an effector kinase of Ras.
“On activation, Ras interacts with the serine͞threonine kinase Raf, an effector kinase of Ras (42,43).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [42] 42. Marshall, C. J. (1996) Nature 383, 127-128.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [43] 43. Baumann, B., Weber, C. K., Troppmaier, J., Whiteside, S., Israel, A., Rapp, U. R. & Wirth, T. (2000) Proc. Natl. Acad. Sci. USA 97, 4515-4620.
Not checked in the free run.
- Interpretationown data
Alpha1- and beta-adrenergic receptors act in concert to mediate NA-dependent NF-kB activation in THP-1 cells.
“indicating that ␣ 1 -and -adrenergic receptors act in concert to mediate NA-dependent NF-B activation in THP-1 cells.”
Quote in the paperSubstantial claim - Interpretationcitation
NA-mediated adrenergic activation of Ptx-sensitive G proteins results in PI3-kinase and Ras activation.
“Consistent with a recently reported linkage of G proteincoupled receptors to MAPK signaling through PI3-kinase ␥ (41), NA-mediated adrenergic activation of Ptx-sensitive G proteins results in PI3-kinase and Ras activation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] 41. Lopez-Ilsaca, M., Crespo, P., Pellici, P. G., Gutkind, J. S. & Wetzker, R. (1997) Science 275, 394-397.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Study design and conductcitation
Binding activity of the basal transcription factor OCT-1 was determined to exclude differences in nuclear extract quality or nonspecific cell activation.
“To exclude that differences in the quality of the nuclear extracts or nonspecific cell activation account for the induction pattern observed, binding activity of the basal transcription factor OCT-1, known to be in general not activated by stimuli of NF-B (24, 26), was determined.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [24] 24. Hofmann, M., Schiekofer, S., Isermann, B., Kanitz, M., Henkels, M., Joswig, M., Treusch, A., Morcos, M., Weiss, T., Borcea, V., et al. (1999) Diabetologia 42, 222-232.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [26] 26. Ritchie, M. E. (1998) Circulation 98, 1707-1713.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The observation that binding activity of NF-kB, but not of Oct-1, was altered confirms that psychosocial stress elicits a receptor-dependent specific signal rather than a nonspecific cell activation.
“The observation that binding activity of NF-B, but not of Oct-1, was altered (Fig. 1 b and d) further confirms that psychosocial stress elicits a receptor-dependent specific signal rather than a nonspecific cell activation.”
Quote in the paperSubstantial claim - Interpretationown data
These findings point to a central role of MAPK in stress-dependent NF-kB activation in vitro and in vivo.
“These findings point to a central role of MAPK in stress-dependent NF-B activation in vitro and in vivo and are in accordance with a previous report demonstrating NA-dependent ERK-2-phosphorylation in human PBMC (47).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [47] 47. Rouppe van der Voort, C., Kavelaars, A., van de Pol, M. & Heijnen, C. J. (2000) J. Neuroimmunol. 108, 82-91.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Induction of NF-kB is in part dependent on the interaction of NA with alpha1- and beta-adrenergic receptors.
“Induction of NF-B is in part dependent on the interaction of NA with ␣ 1 -and -adrenergic receptors.”
Quote in the paperSubstantial claim - Interpretationown data
Mental stress can be converted into functionally significant cellular NF-kB activation.
“These data confirm that mental stress can be converted into functionally significant cellular NF-B activation.”
Quote in the paperSubstantial claim - Interpretationcitation
It is more likely that repeated exposure to adverse, i.e., stressful, life events with failure to habituate biologically to these circumstances will convey the well documented disease outcomes.
“It is more likely that a repeated exposure to adverse, i.e., stressful, life events with failure to habituate biologically to these circumstances will convey the well documented disease outcomes (56).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56] 56. McEwen, B. S. (1998) N. Engl. J. Med. 338, 171-179.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
Activated MAPKs induce downstream signaling pathways that result in phosphorylation and degradation of IκBα and subsequent activation and nuclear translocation of NF-κB.
“Activated MAPKs induce as-yet uncharacterized downstream-located signaling pathways that result in phosphorylation and degradation of the NF-B-specific cytoplasmic inhibitor IB␣ and subsequent activation and nuclear translocation of NF-B.”
Quote in the paperSubstantial claim - Premisecitation
Expression of β2-adrenergic receptors is at least in part regulated by NF-κB.
“The fact that expression of  2 -adrenergic receptors itself is at least in part regulated by NF-B (61)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [61] 61. Aksoy, M. O., Bin, W., Yang, Y., Yun-You, D. & Kelsen, S. G. (2001) Am. J. Physiol. 281, L1271-L1278.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Study design and conductown data
NF-κB binding was confirmed by competing with a 160-fold molar excess of unlabeled NF-κB consensus oligonucleotides.
“NF-B binding was confirmed by competing with a 160-fold molar excess of unlabeled NF-B consensus oligonucleotides (b; cons, lane 10).”
- Also stated in: § Modulation of NF-B Activation. · plain
“To confirm NF-B binding, nuclear extract from an immobilized mouse was competed with a 160-fold molar excess of unlabeled NF-B consensus oligonucleotides (lane 10).”
Quote in the paperSubstantial claim - Also stated in: § Modulation of NF-B Activation. · plain
- Interpretationown data
G proteins activate directly or indirectly via PI3-kinase Ras interacting with its effector kinase Raf.
“G proteins activate directly or indirectly via PI3-kinase Ras interacting with its effector kinase Raf subsequently.”
Quote in the paperSubstantial claim - Interpretationcitation
In chronic diseases with abundant RAGE ligands, psychosocial stress-induced NF-κB activation might be amplified and converted to a constant threat.
“In chronic diseases, in which these RAGE ligands are abundantly expressed, psychosocial stress-induced NF-B activation might not only be amplified, but converted to a constant threat (25,57).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [25] 25. Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P. M., Chen, J., Hong, M., Luther, T., Henle, T., Kloting, I., et al. (2001) Diabetes 50, 2792-2808.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [57] 57. Schmidt, A. M. & Stern, D. (2000) Circ. Res. 87, 722-724.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
Noradrenaline-dependent adrenergic stimulation results in activation of NF-κB in vitro and in vivo.
“Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-B in vitro and in vivo.”
Quote in the paperSubstantial claim - Premisecitation
High concentrations of noradrenaline induce phosphorylation of α1(a)-adrenergic receptors and thereby block receptor action.
“High concentrations of NA have been described to induce phosphorylation of ␣ 1(a) -adrenergic receptors and thereby block receptor action (58).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58] 58. Vazquez-Prado, J., Medina, L. C., Romero-Avila, M. T., Gonzales-Espinosa, C. & Garcia-Sainz, J. A. (2000) J. Biol. Chem. 275, 6553-6559.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Large differences in the time required to down-regulate NF-κB activation to baseline cannot simply be explained by cortisol's NF-κB inhibiting properties because cortisol levels did not significantly differ in the volunteers studied.
“A further level of complexity is added by the large differences in the time required to down-regulate NF-B activation to baseline, which cannot simply be explained by the NF-B activation inhibiting properties of cortisol (59) because cortisol levels did not significantly differ in the volunteers studied.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [59] 59. Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A. & Karin, M. (1995) Science 270, 286-290.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Pathophysiologically relevant cellular perturbants such as high glucose, advanced glycation end products, S100-proteins, and amyloid-β peptides induce NF-κB and perpetuate its activation by engaging RAGE.
“A number of pathophysiologically relevant cellular perturbants such as high glucose, advanced glycation end products, S100-proteins, and amyloid- peptides have been shown not only to induce NF-B, but also to perpetuate its activation by engagement of the receptor RAGE (25,40,57).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [25] 25. Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P. M., Chen, J., Hong, M., Luther, T., Henle, T., Kloting, I., et al. (2001) Diabetes 50, 2792-2808.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [40] 40. Evans, J. L., Goldfine, I. D., Maddux, B. A. & Grodsky, G. M. (2002) Endocr. Rev. 23, 599-622.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [57] 57. Schmidt, A. M. & Stern, D. (2000) Circ. Res. 87, 722-724.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
Individual proinflammatory responses to psychosocial stress might determine the extent of anti-inflammatory down-regulation.
“implying that the individual proinflammatory responses to psychosocial stress might determine the extent of the antiinflammatory down-regulation.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Low doses of adrenaline might act synergistically with noradrenaline and thereby further increase NF-κB activation.
“This implies that low doses of AD might act synergistically with NA and thereby further increase NF-B activation.”
Quote in the paperSubstantial claim - Premisecitation
Failure to habituate biologically to life events conveys well-documented disease outcomes.
“life events with failure to habituate biologically to these circumstances will convey the well documented disease outcomes (56).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56] 56. McEwen, B. S. (1998) N. Engl. J. Med. 338, 171-179.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
β-adrenergic agonists exert anti-inflammatory effects in monocytic cells by increasing cytoplasmic levels of IκBα.
“-adrenergic agonists exert antiinflammatory effects in monocytic cells by increasing cytoplasmic levels of IB␣ (60)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [60] 60. Farmer, P. & Pugin, J. (2000) Am. J. Physiol. 279, L675-L682.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
NF-κB is a good candidate to convert psychosocial stress into cellular activation.
“Therefore, NF-B is a good candidate to convert psychosocial stress into cellular activation.”
Quote in the paperSubstantial claim- Rests on an assumption: Various genes up-regulated in atherosclerosis and by psychosocial stress are controlled by NF-κB.
- Interpretationown data
The data presented here provide strong evidence for a specific pathway through which psychosocial stress signals are converted into mononuclear cell activation.
“The data presented here provide strong evidence for a specific pathway through which psychosocial stress signals are converted into mononuclear cell activation (Fig. 4d).”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 18
- May combine two claims. 28
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNF-kB-binding activity consisted of the NF-kB heterodimer p50/p65.
“NF-B-binding activity consisted of the NF-B heterodimer NF-Bp50͞p65 (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIL-6 mRNA was induced in response to immobilization and reduced in the presence of prazosin.
“IL-6-mRNA, in part regulated by NF-B, was also induced in response to immobilization and reduced in the presence of prazosin (data not shown).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn 17 of 19 volunteers, NF-κB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min.
“In 17 of 19 volunteers, NF-B was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min.”
- Also stated in: § Modulation of NF-B Activation. · plain
“Psychosocial stress induces the transcription factor NF-B in healthy volunteers undergoing the TSST.”
Quote in the paperSubstantial claim- Rests on an assumption: PBMC play a role in diseases such as atherosclerosis.
- Rests on an assumption: PBMC are a valid window into the body for assessing NF-κB activation.
- Also stated in: § Modulation of NF-B Activation. · plain
May combine two claims.
Findingown dataOnly noradrenaline resulted in a dose- and time-dependent induction of NF-κB and NF-κB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated PI3-kinase, Ras/Raf, and MAPK activation.
“Only noradrenaline resulted in a dose-and time-dependent induction of NF-B and NF-B-dependent gene expression, which depended on pertussis-toxin-sensitive G proteinmediated phosphophatidylinositol 3-kinase, Ras͞Raf, and mitogenactivated protein kinase activation.”
- Also stated in: § Modulation of NF-B Activation. · plain
“Physiological concentrations of NA induce functionally significant NF-B-binding activity in cultured THP-1 monocytic cells.”
Quote in the paperSubstantial claim- Rests on an assumption: THP-1 monocytic cells model mononuclear cell activation in vivo.
- Also stated in: § Modulation of NF-B Activation. · plain
May combine two claims.
Findingown dataImmobilization stress in β-globin transgenic mice resulted in increased β-globin expression, which could be reduced by the α1-adrenergic inhibitor prazosin.
“Immobilization resulted in increased -globin expression, which could be reduced in the presence of the ␣1-adrenergic inhibitor prazosin.”
- Also stated in: § Modulation of NF-B Activation. · plain
“Immobilization stress induces NF-B-dependent gene expression in -globin transgenic mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The β-globin transgene in mice is strictly NF-κB-controlled.
- Rests on an assumption: Immobilization stress in mice models psychosocial stress.
- Also stated in: § Modulation of NF-B Activation. · plain
May combine two claims.
PremisecitationConstitutive expression of the beta-globin transgene is restricted to lymphoid tissues, whereas activation of the NF-kB p50/p65 heterodimer confers inducible transgene activation in all cells.
“Constitutive expression of the -globin transgene is restricted to lymphoid tissues (36), whereas activation of the NF-B p50͞p65-heterodimer confers inducible transgene activation in all cells (36).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] 36. Lernbecher, T., Muller, U. & Wirth, T. (1993) Nature 365, 767-770.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ A mechanism converting psychosocial stress into mononuclear cell activationThe cardiovascular system is a target of psychosocial stress, which is associated with exercise-induced myocardial ischemia, increases in blood pressure, heart rate, arrhythmias, development of arteriosclerosis, and death.
“T he cardiovascular system is a target of psychosocial stress associated with exercise-induced myocardial ischemia, increases in blood pressure, heart rate, and arrythmias, development of arteriosclerosis, and death (1)(2)(3)(4).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (1)(2)(3)(4)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataThe stress-dependent increase in ACTH, cortisol, and catecholamines parallels the TSST-mediated NF-kB induction, suggesting rapid NF-kB activation after a brief period of psychosocial stress.
“was paralleled by the stress-dependent increase in ACTH, cortisol, and catecholamines, suggesting a rapid NF-B activation after a brief period (i.e., 10 min) of psychosocial stress.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ A mechanism converting psychosocial stress into mononuclear cell activationBehavioral interventions, stress reduction, and stress management demonstrated benefits over and above usual medical care in hypertensive African Americans and in cardiac patients with evidence of myocardial ischemia.
“Consistently, behavioral interventions, stress reduction, and stress management demonstrated benefits over and above usual medical care in hypertensive African Americans (13) and in cardiac patients with evidence of myocardial ischemia (14)(15)(16)(17)(18).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [13] 13. Castillo-Richmond, A., Schneider, R. H., Alexander, C. N., Cook, R., Myers, H., Nidich, S., Haney, C., Rainforth, M. & Salerno, J. (2000) Stroke 31, 568-573.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites (14)(15)(16)(17)(18)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ A mechanism converting psychosocial stress into mononuclear cell activationIncreased NF-kB activation has been described in blood lymphocytes of women stressed by the experience of breast biopsy.
“Increased NF-B activation also has been described in blood lymphocytes of women stressed by the experience of breast biopsy (31)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] 31. Nagabhushan, M., Mathews, H. L. & Witek-Janusek, L. (2001) Brain Behav. Immun. 15, 78-84.
Not checked in the free run.
May combine two claims.
Premisecitation§ A mechanism converting psychosocial stress into mononuclear cell activationIntervention studies in cynomolgus monkeys show activation of these processes by mental stress and reduction of vascular dysfunction and disease by reducing psychosocial stress through beta-adrenergic blockade.
“Intervention studies in cynomolgus monkeys support this concept, showing not only activation of these processes by mental stress but also reduction of vascular dysfunction and disease by reducing psychosocial stress through -adrenergic blockade (8)(9)(10)(11)(12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (8)(9)(10)(11)(12)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ A mechanism converting psychosocial stress into mononuclear cell activationOne observation pointing to a potential mechanism is the induction of inflammatory reactions and simultaneous decrease of anti-inflammatory reactions leading to enhanced cytokine release and monocytic cell activation.
“One observation pointing to a potential mechanism is the induction of inflammatory reactions and the simultaneous decrease of antiin-flammatory reactions leading to enhanced cytokine release and monocytic cell activation (19)(20)(21)(22)(23).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (19)(20)(21)(22)(23)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ A mechanism converting psychosocial stress into mononuclear cell activationPotential toxic elements in the personality construct such as hostility, anger, cynicism, mistrust, and unhealthy lifestyle, as well as social isolation, lack of social support, and work-related stress, increase the risk for cardiovascular disease.
“Potential toxic elements in the personality construct such as hostility, anger, cynicism, mistrust, and unhealthy lifestyle (1,5,6), as well as social isolation (5), lack of social support (6), and work-related stress (7), increase the risk for cardiovascular disease”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] 1. Rozanski, A., Blumenthal, J. A. & Kaplan, J. (2000) Circulation 99, 2192-2217.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [5] 5. Stansfeld, S. A., Fuhrer, R., Shipley, M. J. & Marmot, M. G. (2002) Int. J. Epidemiol. 31, 248-255.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [6] 6. Berkman, L. F., Leo-Summers, L. & Horwitz, R. I. (1992) Ann. Intern. Med. 117, 1003-1009.
Not checked in the free run.
- cites [7] 7. Bosma, H., Peter, R., Siegrist, J. & Marmot, M. (1998) Am. J. Public Health 88, 68-74.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
PremisecitationThioctic acid is known to inhibit reactive oxygen species-mediated NF-kB activation.
“Thioctic acid (2 mM), known to inhibit reactive oxygen species-mediated NF-B activation (38)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] 38. Packer, L. (1998) Drug Metab. Rev. 30, 245-275.
Not checked in the free run.
May combine two claims.
InterpretationcitationNA-dependent activation of similar signal transduction cascades in various cell types implies that the cellular response to stress uses comparable pathways and suggests that monitoring stress-dependent cellular activation in PBMC might allow estimation of the effect of psychosocial stress on allostasis and its impact on the allostatic load.
“NA-dependent activation of similar signal transduction cascades in various cell types implies that the cellular response to stress uses comparable pathways and suggests that monitoring stress-dependent cellular activation in PBMC might allow estimation of the effect of psychosocial stress on allostasis and its impact on the allostatic load (55).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [55] 55. Karlamangla, A., Singer, B., McEwen, B. S., Rowe, J. & Seeman, T. (2002) J. Clin. Epidemiol. 55, 696-710.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenProcedures in this study were approved by the Animal Care and Use Committee at the Regierungspraesidium Karlsruhe, Germany.
“Procedures in this study were approved by the Animal Care and Use Committee at the Regierungspra ¨sidium Karlsruhe, Germany.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataHere we present an adrenergic signaling pathway that explains the rapid increase in activation of NF-kB observed in PBMC shortly after exposure to psychosocial stress, linking psychosocial stress to mononuclear cell activation and subsequent changes in the immune system.
“Here we present an adrenergic signaling pathway that explains the rapid increase in activation of the transcription factor NF-B observed in PBMC shortly after exposure to psychosocial stress, thus linking psychosocial stress to mononuclear cell activation and subsequent changes in the immune system.”
Quote in the paperSubstantial claim- Rests on an assumption: Downstream signals converting psychosocial stress into cellular dysfunction and vascular disease are largely unknown.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNF-kB activation is supposed to contribute to the pathophysiology of lifestyle-related diseases such as diabetes mellitus, cardiovascular disease, and atherosclerosis.
“NF-B activation is supposed to contribute to the pathophysiology of lifestylerelated diseases such as diabetes mellitus, cardiovascular disease, and atherosclerosis (24-29, 38, 40, 57)”
Quote in the paperNot a substantial claim0 of 9 sources checked- cites [24] 24. Hofmann, M., Schiekofer, S., Isermann, B., Kanitz, M., Henkels, M., Joswig, M., Treusch, A., Morcos, M., Weiss, T., Borcea, V., et al. (1999) Diabetologia 42, 222-232.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [25] 25. Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P. M., Chen, J., Hong, M., Luther, T., Henle, T., Kloting, I., et al. (2001) Diabetes 50, 2792-2808.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [26] 26. Ritchie, M. E. (1998) Circulation 98, 1707-1713.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [27] 27. Collins, T. & Cybulsky, M. I. (2001) J. Clin. Invest. 107, 255-264.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [28] 28. Breuss, J. M., Cejna, M., Bergmeister, H., Kadl, A., Baumgartl, G., Steurer, S., Xu, Z., Koshelnick, Y., Lipp, J., De Martin, R., et al. (2002) Circulation 105, 633-638.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [29] 29. Yoshimura, S., Morishita, R., Hayashi, K., Yamamoto, K., Nakagami, H., Kaneda, Y., Sakai, N. & Ogihara, T. (2001) Gene Ther. 8, 1635-1642.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [38] 38. Packer, L. (1998) Drug Metab. Rev. 30, 245-275.
Not checked in the free run.
- cites [40] 40. Evans, J. L., Goldfine, I. D., Maddux, B. A. & Grodsky, G. M. (2002) Endocr. Rev. 23, 599-622.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [57] 57. Schmidt, A. M. & Stern, D. (2000) Circ. Res. 87, 722-724.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataThe consistent results obtained in healthy volunteers, animal studies, and studies in vitro provide strong evidence that the mechanism described is not only observed in a single model, but may be applicable to rather different situations with increased NA release as the common denominator.
“The consistent results obtained in healthy volunteers, animal studies, and studies in vitro provide strong evidence that the mechanism described is not only observed in a single model, but may be applicable to rather different situations with increased NA release as the common denominator.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataRT-PCR for beta-actin served as an internal control and confirmed comparable RNA input in each reaction.
“RT-PCR for -actin served as an internal control and confirmed the comparable RNA-input in each reaction (Fig. 2a Lower).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationNA-triggered signaling cascades in mononuclear cells involve PI3-kinase, Ras/Raf, and members of the MAPK family and resemble NA-induced signaling pathways described in vascular cells.
“The NAtriggered signaling cascades in mononuclear cells involve PI3kinase, Ras͞Raf, and members of the MAPK family and thus resemble the NA-induced-signaling pathways described in vascular cells (48)(49)(50)(51)(52)(53)(54), although NF-B activation has not yet been studied in these cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (48)(49)(50)(51)(52)(53)(54)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThere is a linkage of G protein activation to adrenergic signal transduction.
“Consistent with a linkage of G protein activation to adrenergic signal transduction (39)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] 39. Williams, N. G., Zhong, H. & Minnemann, K. P. (1998) J. Biol. Chem. 273, 24624-24632.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationRas is supposed to directly participate in p38-MAPK activation and to represent a signaling target for free radicals and cellular redox stress.
“In addition, Ras is supposed to directly participate in p38-MAPK activation (45) and to represent a signaling target for free radicals and cellular redox stress (46).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [45] 45. McDermott, E. P. & O'Neill, L. A. (2002) J. Biol. Chem. 277, 7808-7815.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [46] 46. Lander, H. M., Ogiste, J. S., Teng, K. K. & Novogrodsky, A. (1995) J. Biol. Chem. 270, 21195-21198.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationRaf can phosphorylate MEK1 and MEK2, which in turn phosphorylate and activate ERK-1 and -2.
“Subsequently, Raf can phosphorylate MEK1 and MEK2 (44), which in turn phosphorylate and activate ERK-1 and -2 (p44͞p42-MAPK) (44).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] 44. Yoshizumi, M., Tsuchiya, K. & Tamaki, T. (2001) J. Med. Invest. 48, 11-24.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrazosin is known to reduce immobilization stress-mediated immediate early gene expression in the mouse brain.
“pretreated with the ␣ 1 -antagonist prazosin (1 mg͞kg), known to reduce immobilization stress-mediated immediate early gene expression in the mouse brain (37).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] 37. Stone, E. A. & Zhang, Y. (1995) Brain Res. 694, 279-286.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataMental stress in humans and rodents results in nuclear translocation of NF-kB and changes in transcriptional activity.
“The observation that mental stress in humans and rodents results in nuclear translocation of NF-B and changes in transcriptional activity thus closes an important gap in understanding the cellular consequences of psychosocial stress.”
Quote in the paperSubstantial claim- Rests on an assumption: Downstream signals converting psychosocial stress into cellular dysfunction and vascular disease are largely unknown.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenReactions lacking template RNA or AMV-reverse transcriptase served as internal controls.
“Reactions lacking template RNA or AMV-reverse transcriptase served as internal controls.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductcitationPBMC were adjusted to the same cell number before NF-kB-binding activity was determined.
“Because psychosocial stress has been described to increase the lymphocyte and monocyte population (21), PBMC had been adjusted to the same cell number before NF-B-binding activity was determined.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] 21. Goebel, M. U., Mills, P. J., Irwin, M. R. & Ziegler, M. G. (2000) Psychosom. Med. 62, 591-598.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationG protein-coupled receptors are linked to MAPK signaling through PI3-kinase gamma.
“Consistent with a recently reported linkage of G proteincoupled receptors to MAPK signaling through PI3-kinase ␥ (41)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] 41. Lopez-Ilsaca, M., Crespo, P., Pellici, P. G., Gutkind, J. S. & Wetzker, R. (1997) Science 275, 394-397.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataNA-dependent adrenergic signal transduction is mediated by Ptx-sensitive G proteins inducing PI3-kinase and Ras/Raf signaling that results in MAPK activation and subsequent NF-kB induction.
“The NAdependent adrenergic signal transduction is mediated by Ptxsensitive G proteins inducing PI3-kinase and Ras͞Raf signaling that results in MAPK activation and subsequent NF-B induction (Fig. 4).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningA cooperative action of catecholamines regulating receptor expression and other stress response modifiers might act in concert in controlling cell activation.
“A cooperative action of catecholamines regulating receptor expression and other stress response modifiers might act in concert in controlling cell activation.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationActivation of NF-κB might terminate itself by a negative IκBα-dependent feedback loop and by induction of β2 receptors that antagonize the proinflammatory challenge.
“indicates that the activation of NF-B might not only be terminating itself by a negative IB␣-dependent feed back loop (27), but that activation of NF-B by ␣-adrenergic receptors terminates itself by induction of  2 receptors able to antagonize the proinflammatory challenge (60).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [27] 27. Collins, T. & Cybulsky, M. I. (2001) J. Clin. Invest. 107, 255-264.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [60] 60. Farmer, P. & Pugin, J. (2000) Am. J. Physiol. 279, L675-L682.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNA-dependent ERK-2-phosphorylation in human PBMC has been reported.
“in accordance with a previous report demonstrating NA-dependent ERK-2-phosphorylation in human PBMC (47).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] 47. Rouppe van der Voort, C., Kavelaars, A., van de Pol, M. & Heijnen, C. J. (2000) J. Neuroimmunol. 108, 82-91.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe relation of NF-κB activation to cellular dysfunction and vascular disease has been directly established by genetic overexpression of IκBα and by indirect studies of nuclear NF-κB in vascular disease.
“The relation of NF-B activation to cellular dysfunction and vascular disease has been directly established by using genetic approaches to overexpress the NF-Bspecific inhibitor IB␣ (28) and by indirect studies looking at the presence of cells with nuclear located NF-B in vascular disease (24)(25)(26)(27)29).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [28] 28. Breuss, J. M., Cejna, M., Bergmeister, H., Kadl, A., Baumgartl, G., Steurer, S., Xu, Z., Koshelnick, Y., Lipp, J., De Martin, R., et al. (2002) Circulation 105, 633-638.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [24] 24. Hofmann, M., Schiekofer, S., Isermann, B., Kanitz, M., Henkels, M., Joswig, M., Treusch, A., Morcos, M., Weiss, T., Borcea, V., et al. (1999) Diabetologia 42, 222-232.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [25] 25. Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P. M., Chen, J., Hong, M., Luther, T., Henle, T., Kloting, I., et al. (2001) Diabetes 50, 2792-2808.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
InterpretationreasoningActivation of NF-κB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.
“Activation of NF-B represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe experiment in Fig. 3 was repeated two times with identical results and one representative experiment is shown.
“The experiment was repeated two times with identical results and one representative experiment is shown.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataPsychosocial stress induces noradrenaline that binds to α1- and β-adrenergic receptors, which in turn recruit pertussis-toxin-sensitive G proteins.
“Psychosocial stress induces NA that binds to ␣1and -adrenergic receptors, which in turn recruit Ptx-sensitive G proteins.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe experiments in Fig. 4 were repeated three to five times with identical results and confirmed by NF-κBp65-specific ELISA.
“The experiments were repeated three (b and c) to five (a) times with identical results and confirmed by NF-Bp65-specific ELISA.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationLowering psychosocial stress by β-adrenergic inhibitors and/or stress management leads to reduction of intima media thickness and overall cardiovascular mortality.
“Clinical and experimental studies provide evidence that lowering psychosocial stress by -adrenergic inhibitors (9,11,12) and͞or stress management (13-16) lead to reduction of the intima media thickness (13) and the overall cardiovascular mortality (14,15).”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [9] 9. Kaplan, J. R., Manuck, S. B., Adams, M. R., Weingand, K. W. & Clarkson, T. B. (1987) Circulation 76, 1365-1372.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11] 11. Kaplan, J. R. & Manuck, S. B. (1994) Am. Heart J. 128, 1316-1328.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12] 12. Skantze, H. B., Kaplan, J., Petterson, K., Manuck, S., Blomqvist, M., Kyes, R., Williams, K. & Bondjers, G. (1998) Atherosclerosis 136, 153-161.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13] 13. Castillo-Richmond, A., Schneider, R. H., Alexander, C. N., Cook, R., Myers, H., Nidich, S., Haney, C., Rainforth, M. & Salerno, J. (2000) Stroke 31, 568-573.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14] 14. Blumenthal, J. A., Babyak, M., Wei, J., O'Connor, C., Waugh, R., Eisenstein, E., Mark, D., Sherwood, A., Woodley, P. S., Irwin, R. J., et al. (2002) Am. J. Cardiol. 89, 164-168.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [15] 15. Denollet, J. & Brutsaert, D. L. (2001) Circulation 104, 2018-2023.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [16] 16. King, M. S., Carr, T. & D'Cruz, C. (2002) Aust. Fam. Physician 31, 164-168.
Not checked in the free run.
May combine two claims.
InterpretationreasoningRaf phosphorylates MEK-1 and -2, which activates p44/p42-MAPK.
“Raf phosphorylates MEK-1 and -2, which activates p44͞p42-MAPK.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenRas can directly induce p38-MAPK activation.
“In addition, Ras, which is a target of cellular oxidative stress, can directly induce p38-MAPK activation.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Downstream signals converting psychosocial stress into cellular dysfunction and vascular disease are largely unknown.
“Further downstream signals converting psychosocial stress into cellular dysfunction and finally into vascular disease are still largely unknown.”
“much less is known about the molecular mechanisms converting psychosocial stress into cellular activation.”
The paper relies on this without support.
The neuroendocrine response to stress involves an interplay among the hypothalamus, pituitary gland, adrenal medulla, and sympathetic nerve terminals.
“Recent data have indicated an interplay among hypothalamus, pituitary gland, adrenal medulla, and sympathetic nerve terminals as the neuroendocrine response to stress.”
The paper relies on this without support.
Various genes up-regulated in atherosclerosis and by psychosocial stress are controlled by NF-κB.
“Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor B (NF-B).”
The paper relies on this without support.
PBMC play a role in diseases such as atherosclerosis.
“because PBMC play a role in diseases such as atherosclerosis.”
The paper relies on this without support.
PBMC are a valid window into the body for assessing NF-κB activation.
“as a window into the body”
The paper relies on this without support.
The β-globin transgene in mice is strictly NF-κB-controlled.
“mice transgenic for a strictly NF-B-controlled -globin transgene”
The paper relies on this without support.
Immobilization stress in mice models psychosocial stress.
“To model this response, mice transgenic for a strictly NF-B-controlled -globin transgene were stressed by immobilization.”
The paper relies on this without support.
THP-1 monocytic cells model mononuclear cell activation in vivo.
“cultured THP-1 monocytic cells”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Under normal conditions, catecholamines and glucocorticoids regulate inflammation through inhibition of proinflammatory cytokines (IL-6, IL-1β, TNF-α) and stimulation of anti-inflammatory cytokines (IL-4, IL-10, IL-13) by exerting action in the cytoplasm of immune cells.
“Under normal conditions, catecholamines and glucocorticoids regulate inflammation through the inhibition of proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, and the stimulation of anti-inflammatory cytokines, such as IL-4, IL-10, and IL-13 [38], by exerting action in the cytoplasm of immune cells.”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [38]
Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredCombining chronic HCC measurements with acute cortisol assessments provides a comprehensive understanding of the stress response and its relevance to psychiatric and stress-related disorders.
“Combining chronic HCC measurements with acute cortisol assessments provides a comprehensive understanding of the stress response and its relevance to psychiatric and stress-related disorders [37,38].”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [38]
The Results (page unavailable) show that cortisol increased after an acute psychosocial stress test and served as a marker of the endocrine stress response. The paper does not assess chronic hair cortisol concentration (HCC), evaluate combining chronic and acute measurements, or establish the claimed relevance to psychiatric disorders. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNormal cortisol secretion acts inhibitory toward cells that produce peripheral cytokines, mitigating inflammation.
“Normal cortisol secretion acts inhibitory toward cells that produce peripheral cytokines, mitigating inflammation.”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [38]
The ‘Modulation of NF-B Activation’ section describes cortisol as having NF-B-activation-inhibiting properties, and the introduction links NF-B activation with cytokine release and monocytic cell activation. The paper does not establish that normal cortisol secretion inhibits cytokine-producing cells or demonstrate the claimed reduction in inflammation. (LLM, conf=0.82)
Experimental — accuracy not yet measuredA laboratory stressor entailing delivering a speech to a judgmental panel activates key inflammatory pathways in peripheral blood mononuclear cells, including NF-κB, and leads to marked increases in circulating pro-inflammatory cytokines such as IL-6.
“The stressor activates key inflammatory pathways in peripheral blood mononuclear cells, including activation of the transcription factor nuclear factor–κB (NF-κB), and leads to marked increases in circulating levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6)3,4.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [4]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIncreased norepinephrine production following stressor exposure induces NFκB activity that activates the immune system and increases cytokine production.
“In contrast, increased norepinephrine production following stressor exposure induces NFκB activity that activates the immune system and increases cytokine production (Bierhaus et al, 2003).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Bierhaus et al, 2003
The Results report that psychosocial stress increased norepinephrine and NF-κB activity, while norepinephrine induced NF-κB activity and IL-6 transcription in cultured monocytes. The Discussion links this pathway to mononuclear cell activation and immune-system changes. The paper does not establish that this pathway increased cytokine production following stress exposure; it measured IL-6 transcription in cultured cells, not cytokine production in the stressed volunteers. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Exposure to the Trier Social Stress Test activates the peripheral inflammatory response via increased NFκB transcriptional activity that results in increased circulating concentrations of IL-6.
“For example, exposure to the laboratory Trier Social Stress Test activates the peripheral inflammatory response via increased NFκB transcriptional activity that results in increased circulating concentrations of IL-6 (Bierhaus et al, 2003).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Bierhaus et al, 2003
The Results report increased NF-κB binding activity in peripheral blood mononuclear cells after the Trier Social Stress Test. They report increased IL-6 transcription in noradrenaline-treated cultured cells and IL-6 mRNA after immobilization stress in mice, but not increased circulating IL-6 concentrations in the volunteers. No page numbers are available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIncreased norepinephrine production in PTSD in response to stressful or threatening stimuli can induce cytokine release.
“This increased norepinephrine production in PTSD in response to stressful or threatening stimuli can induce cytokine release (Bierhaus et al, 2003).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Bierhaus et al, 2003
The Results report that psychosocial stress increased noradrenaline levels in healthy volunteers and that noradrenaline increased IL-6 transcription in cultured monocytes. The paper does not establish this response in people with PTSD or demonstrate cytokine release, as distinct from transcription. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe subsequent immune response occurs via NFκB-dependent and -independent mechanisms.
“The subsequent immune response occurs via NFκBdependent and -independent mechanisms (Bierhaus et al, 2003;Tan et al, 2007).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Bierhaus et al, 2003
The Results and Modulation of NF-B Activation sections describe a stress-related pathway involving NF-κB activation and NF-κB-regulated IL-6 transcription. Our copy does not establish an NF-κB-independent mechanism for the subsequent immune response; the searches for independent pathways found none. Page numbers were not available in the indexed passages. (LLM, conf=0.86)
Experimental — accuracy not yet measuredActivation of adrenergic-β2 receptors stimulates IL-6 and IL-1β secretion from macrophages and monocytes via NFκB and ERK signaling pathways, respectively.
“More specifically, activation of adrenergic-β2 receptors stimulates IL-6 and IL-1β secretion from macrophages and monocytes via NFκB and ERK signaling pathways, respectively (Bierhaus et al, 2003;Tan et al, 2007).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Bierhaus et al, 2003
The Results (page unavailable) show that noradrenaline increased NF-κB activity and IL-6 transcription in THP-1 monocytic cells; blocking β2 receptors reduced the NF-κB response. They do not show IL-6 secretion or establish that β2 activation alone caused the IL-6 increase. The paper also does not report IL-1β secretion from macrophages or monocytes via ERK. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExposure to a psychosocial laboratory stressor can activate an inflammatory response in humans.
“the observation that exposure to a psychosocial laboratory stressor can activate an inflammatory response in humans was a major breakthrough in linking inflammation to depression3,4.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [4]
The predictable growth rate of scalp hair, approximately 1 cm per month, makes the 1 cm hair segment a reflection of the prior month's cortisol production.
“The predictable growth rate of scalp hair, approximately 1 cm per month, makes the 1 cm hair segment a reflection of the prior month’s cortisol production.”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [38]
The Methods section describes measuring salivary cortisol, and the Results describe cortisol changes shortly after a stress test; neither addresses cortisol in hair. Searches for scalp-hair growth, 1-cm hair segments, and monthly cortisol production found no passage supporting the claim. Page numbers were not available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredHair cortisol concentration (HCC), measured from hair samples, offers a promising method for retrospectively assessing chronic stress over extended periods.
“Hair cortisol concentration (HCC), measured from hair samples, offers a promising method for retrospectively assessing chronic stress over extended periods.”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [38]
The Methods section describes salivary cortisol measurement, and the Results report cortisol responses to a brief laboratory stress test. A search of our copy for hair cortisol and retrospective chronic-stress assessment found no passage addressing the claimed method. (LLM, conf=0.76)
Experimental — accuracy not yet measuredNF-κB is a key bridge for stress-induced increases in proinflammatory cytokines and their genes.
“NF-κB appears to be a prime bridge for stress-induced increases in proinflammatory cytokines and the genes that control their expression (5).”
From Stress, Food, and Inflammation: Psychoneuroimmunology and Nutrition at the Cutting Edge (2010) · cites this paper as [5]
Stressful events and depression can influence inflammation through the same pathways as diet.
“Behavioral studies have demonstrated that stressful events and depression can also influence inflammation through these same processes.”
From Stress, Food, and Inflammation: Psychoneuroimmunology and Nutrition at the Cutting Edge (2010) · cites this paper as [5]
Acute psychosocial stress stimulates inflammatory signaling molecules.
“Experimental data indicate that acute psychosocial stress (e.g., public speaking, mental arithmetic) stimulates inflammatory signaling molecules194, and these responses are exaggerated in patients with depression190.”
From Psychobiological factors of resilience and depression in late life (2019) · cites this paper as [194]
Norepinephrine-dependent adrenergic stimulation activates NF-kB, which activates gene expression of several inflammatory mediators.
“Norepinephrine-dependent adrenergic stimulation activates transcription factor nuclear factor kappa B (NF-κB), an intracellular signaling molecule that activates gene expression of several inflammatory mediators”
From Close relationships, inflammation, and health (2010) · cites this paper as Bierhaus et al., 2003
Psychosocial stress can directly provoke proinflammatory cytokine production in the absence of infection or injury.
“Psychosocial stress can directly provoke proinflammatory cytokine production in the absence of infection or injury.”
From Close relationships, inflammation, and health (2010) · cites this paper as Bierhaus et al., 2003
Repeated or severe stressor exposure, in the absence of pathogenic disease, increases inflammatory proteins in tissues and blood in humans and animals.
“repeated or severe stressor exposure, in the absence of pathogenic disease, increases affective dysregulation and inflammatory proteins in tissues and blood in humans (Bierhaus et al, 2003;Pace et al, 2006) and animals (Maslanik et al, 2012a, b).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Bierhaus et al, 2003
Increased sympathetic nervous system activity increases pro-inflammatory cytokine production, whereas parasympathetic activity decreases it.
“Similarly, increased activity of the sympathetic nervous system increases pro-inflammatory cytokine production, whereas parasympathetic activity has the opposite effect.6,7”
From Sleep Deprivation and Circadian Disruption (2015) · cites this paper as [7]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Cortisol sample type differs between Methods and Results
MinorThe Methods say cortisol was measured in saliva, but the Results describe the cortisol measurements as plasma levels.
“ACTH and cortisol plasma levels served as markers of the endocrine stress response”
“Salivary cortisol levels were determined by a timeresolved immunoassay with fluorometric detection as described (33).”
AFC result points to the wrong figure
MinorThe text assigns the AFC inhibitor result to Fig. 3b, lane 8, whereas the Fig. 4 caption assigns AFC to panel b, lane 8. Fig. 3b instead describes a noradrenaline concentration experiment.
“the farnesyl transferase inhibitor AFC (50 M; Fig. 3b, lane 8), which inhibits Ras activation.”
“AFC (50 M, lane 8), and H7 (100 M, lane 9) (b)”
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BackgroundPsychological Distress as a Risk Factor for Cardiovascular Events
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Effects of social isolation on glucocorticoid regulation in social mammals
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Computational identification of gene–social environment interaction at the human <i>IL6</i> locus
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The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D)
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Aggression, Social Stress, and the Immune System in Humans and Animal Models
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Self-citation
- Authors
- Bierhaus, A., Wolf, J., Andrassy, M., Rohleder, N., Humpert, P. M., Petrov, D., Ferstl, R., von Eynatten, M., Wendt, T., Rudofsky, G., Joswig, M., Morcos, M., Schwaninger, M., McEwen, B., Kirschbaum, C., & Nawroth, P. P.
- Affiliations
- Heidelberg University (DE)
- Department of Medicine I and Department of Neurology, University of Heidelberg, Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany; Institute of Experimental Psychology II, University of Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany; Department of Psychology, University of Kiel, Olshausenstrasse 40, 24098 Kiel, Germany; and Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10021
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-02-10
- Volume
- 100
- Issue
- 4
- Pages
- 1920-1925
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC149934
- OpenAlex
- W2151454086
- Cited by
- 926
- References
- 62
- Citations by year
- 2026: 14 · 2025: 34 · 2024: 29 · 2023: 46 · 2022: 45 · 2021: 41 · 2020: 50 · 2019: 51 · 2018: 38 · 2017: 39 · 2016: 46 · 2015: 56 · 2014: 51 · 2013: 36 · 2012: 57
- FWCI
- 7.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- psychosocial stress, NF-κB, mononuclear cells, atherosclerosis, catecholamines, cortisol, norepinephrine, adrenergic signaling
- MeSH terms
- Adrenocorticotropic Hormone, Adult, Animals, Base Sequence, Cell Line, Epinephrine, Female, Humans, Hydrocortisone
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