Prolyl Isomerase Pin1 Protects Mice from Endotoxin Shock
Open accessAbstract
BACKGROUND: Prolyl isomerase Pin1 may be involved in innate immunity against microbial infection, but the mechanism how Pin1 controls the innate immunity is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Injection of lipopolysaccharide (LPS) into the mice induces inflammatory pulmonary disorder and sometimes the serious damages lead to death. Comparing to the wild-type (WT) mice, the Pin1⁻/⁻ mice showed more serious damages in lung and the lower survival rate after the LPS injection. We compared the levels of typical inflammatory cytokines. Pin1⁻/⁻ mice overreacted to the LPS injection to produce inflammatory cytokines, especially IL-6 more than WT mice. We showed that Pin1 binds phosphorylated PU.1 and they localize together in a nucleus. These results suggest that Pin1 controls the transcriptional activity of PU.1 and suppresses overreaction of macrophage that causes serious damages in lung. CONCLUSIONS/SIGNIFICANCE: Pin1 may protect the mice from serious inflammation by LPS injection by attenuating the increase of IL-6 transcription of the mouse macrophages.
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Written from the paper’s full text.
TL;DR
Pin1 deficiency worsens LPS-induced inflammation and mortality in mice, with Pin1−/− mice showing more severe lung injury and higher IL-6 production than wild-type mice. Pin1 appears to bind phosphorylated PU.1 and suppress LPS-induced IL-6 transcription in macrophages.
Key findings
- After intraperitoneal LPS, Pin1−/− mice had a shorter median survival time than WT mice: 59.8±12.4 h vs 98.7±0.84 h, and showed more serious lung damage.
- At 24 h after LPS, serum TNFα increased 2.5-fold in WT and 3-fold in Pin1−/− mice, while IL-6 increased 3-fold in WT and 10-fold in Pin1−/− mice.
- In macrophages, IL-6 mRNA was higher in Pin1−/− mice than WT, most significantly at 4 h after LPS; TNFα mRNA and TLR4 transcription were similar. Pin1 inhibition by PiB elevated IL-6 transcription, and Pin1 overexpression decreased LPS-induced IL-6 but not TNFα.
- Pin1 bound phosphorylated PU.1 at the Ser119-Pro site via its WW domain, and Pin1 plus PU.1 localized together in the nucleus.
Methods
- 15–20-week-old WT and Pin1−/− mice were injected intraperitoneally with LPS at 10 µg/g body weight, monitored for survival, and tissues including lung, liver, kidney, and spleen were examined histologically.
- Serum cytokines were measured by EIA at 24 h; peritoneal macrophages and RAW264.7 cells were stimulated with LPS, and TNFα, IL-6, and TLR4 mRNA were analyzed by RT-PCR/quantitative real-time PCR with β-actin normalization.
- Pin1 function was tested using the Pin1-specific inhibitor PiB and Pin1 overexpression in RAW264.7 cells; Pin1–PU.1 interaction was assessed by GST pull-down assays with Pin1 mutants and PU.1 mutants, and colocalization by immunofluorescent staining in COS7 cells.
Limitations
- The paper states that it remains unknown how Pin1 specifically suppresses IL-6 transcription after LPS stimulation, and that IL-6 up-regulation is probably not the only cause of severe inflammation and early death in Pin1−/− mice.
- The paper states that further study is needed to disclose the precise molecular mechanisms by which Pin1 selectively inhibits TLR-dependent genes.
- Evident from the text: survival and histology experiments used n=5 per genotype, and some findings on MCP-1 and macrophage chemotactic activity are described as “data no shown,” limiting assessment of those claims.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
4 of 14 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Pin1 prevents the production of prostaglandin E2 in MAEC by regulating the degradation of cyclooxygenase-2 induced by LPS.
“Pin1 prevents the production of prostaglandin E2 in MAEC by regulating the degradation of cyclooxygenase-2 induced by LPS [9].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Liu T Schneider RA Shah V Huang Y Likhotvorik RI 2009 Protein Nerve in Mitosis Gene A Interacting-1 (Pin1) regulates calpain activity and the degradation of cyclooxygenase-2 in endothelial cells. J Inflamm 6 20 PMC2708161 19545424 source
The Results (page unavailable) report that PIN1 knockdown increased COX-2–mediated prostaglandin E2 production in MAEC, and the Discussion links PIN1 to COX-2 degradation. The claim omits a decisive condition: the cells were treated with LPS plus IFN; the Results say LPS alone did not induce COX-2. The paper supports PIN1 restraining, rather than categorically preventing, this response. (LLM, conf=0.89)
Experimental — accuracy not yet measured
- Findingown data
After LPS injection, Pin1−/− mice show more serious lung damage than WT mice.
“Comparing to the wild-type (WT) mice, the Pin1−/− mice showed more serious damages in lung and the lower survival rate after the LPS injection.”
- Also stated in: § Pin1 suppressed LPS-induced inflammation · plain
“As a result, we found that LPS injection caused excessive lung injury in Pin1−/− mice than WT mice (Figure 2).”
Quote in the paperSubstantial claim - Also stated in: § Pin1 suppressed LPS-induced inflammation · plain
- Findingown data
Pin1 binds phosphorylated PU.1.
“We showed that Pin1 binds phosphorylated PU.1 and they localize together in a nucleus.”
- Also stated in: § Interaction of Pin1 with PU.1 · plain
“Stimulation of a human acute monocytic leukemia cell line, THP-1 with PMA increased the PU.1 that bound Pin1-beads, but phosphatase treatment decreased the amount of PU.1 (Figure 5a).”
- Also stated in: § Discussion · plain
“We found that Pin1 binds phosphorylated Ser119 –Pro in PU.1 at the WW domain and the complex localizes in a nucleus.”
Quote in the paperSubstantial claim - Also stated in: § Interaction of Pin1 with PU.1 · plain
- Findingown data
Pin1 and PU.1 localize together in a nucleus.
“We showed that Pin1 binds phosphorylated PU.1 and they localize together in a nucleus.”
- Also stated in: § Colocalization of Pin1 and PU.1 · plain
“But transfection of the same cell with both cDNAs together made both proteins localize in a nucleus (Figure 6b).”
- Also stated in: § Discussion · plain
“We found that Pin1 binds phosphorylated Ser119 –Pro in PU.1 at the WW domain and the complex localizes in a nucleus.”
Quote in the paperSubstantial claim - Also stated in: § Colocalization of Pin1 and PU.1 · plain
- Findingown data
After LPS injection, Pin1−/− mice have a lower survival rate than WT mice.
“Comparing to the wild-type (WT) mice, the Pin1−/− mice showed more serious damages in lung and the lower survival rate after the LPS injection.”
- Also stated in: § Pin1 suppressed LPS-induced inflammation · plain
“WT mice showed the same symptoms as Pin1−/− mice, but they were less severely affected and survived significantly longer than Pin1−/− mice (Figure 1).”
Quote in the paperSubstantial claim - Also stated in: § Pin1 suppressed LPS-induced inflammation · plain
- Findingown data
Over-expression of Pin1 in RAW264.7 cells does not decrease LPS-induced TNFα transcription.
“Additionally, over-expression of Pin1 in RAW264.7 results in decrease of LPS-induced IL-6 transcription, but not TNFα (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
Pin1 protein expression level in WT macrophages was not changed by LPS stimulation.
“the expression level of Pin1 protein in WT macrophages was not changed by LPS stimulation (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
Over-expression of Pin1 in RAW264.7 cells decreases LPS-induced IL-6 transcription.
“Additionally, over-expression of Pin1 in RAW264.7 results in decrease of LPS-induced IL-6 transcription, but not TNFα (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
In RAW264.7 cells stimulated with LPS, pretreatment with PiB did not affect TNFα mRNA level.
“Although the TNFα mRNA level was not affected by the PiB treatment, the transcription level of IL-6 was significantly elevated in the cells- pretreated with PiB (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Pin1W34A (WW domain mutant) did not bind PU.1.
“Although whole Pin1 and PPIase domain mutant, Pin1R68/69A bound PU.1, WW domain mutant, Pin1W34A did not bind PU.1.”
Quote in the paperSubstantial claim - Findingown data
pSer16-Pin1 level in RAW264.7 treated with LPS was lower than control between 4 h and 10 h after treatment.
“The pSer16-Pin1 level in RAW264.7- treated with LPS was lower than the control between 4 h–10 h after the treatment (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
TNFα mRNA levels in macrophages from WT and Pin1−/− mice after LPS injection were similar.
“The TNFα mRNA levels of the macrophages in the WT and Pin1−/− mice after LPS-injection were similar.”
Quote in the paperSubstantial claim - Findingown data
TLR4 transcription level in Pin1−/− macrophages was similar to that of WT.
“The transcription level of TLR4 of Pin1−/− macrophages was similar to that of WT (Figure 3C)”
Quote in the paperSubstantial claim - Findingown data
PU.1 binds Pin1 at the S119-Pro site specifically.
“These results showed that PU.1 bound S119-Pro site specifically.”
Quote in the paperSubstantial claim - Findingown data
In RAW264.7 cells stimulated with LPS, pretreatment with Pin1-specific inhibitor PiB significantly elevated IL-6 transcription.
“Although the TNFα mRNA level was not affected by the PiB treatment, the transcription level of IL-6 was significantly elevated in the cells- pretreated with PiB (Figure 4B).”
Quote in the paperSubstantial claim - Interpretationown data
Pin1−/− mice overreact to LPS injection to produce inflammatory cytokines, especially IL-6, more than WT mice.
“Pin1−/− mice overreacted to the LPS injection to produce inflammatory cytokines, especially IL-6 more than WT mice.”
Quote in the paperSubstantial claim - Interpretationown data
Pin1 may protect mice from serious inflammation by LPS injection by attenuating the increase of IL-6 transcription of mouse macrophages.
“Pin1 may protect the mice from serious inflammation by LPS injection by attenuating the increase of IL-6 transcription of the mouse macrophages.”
- Also stated in: § Pin1 suppressed LPS-induced inflammation · hedged
“These results indicate that Pin1 may protect mice from serious inflammation by regulating expression of IL-6 after LPS-injection.”
Quote in the paperSubstantial claim - Also stated in: § Pin1 suppressed LPS-induced inflammation · hedged
- Interpretationown data
Pin1 acts at downstream of TLR4 to inhibit LPS-induced IL-6 transcription.
“In this report, we have shown that Pin1 selectively inhibits LPS-induced IL-6 transcription at the downstream of TLR4 in macrophages.”
Quote in the paperSubstantial claim - Interpretationown data
Pin1 selectively suppresses LPS-induced IL-6 transcription.
“These results indicate that Pin1 is activated by LPS stimulation and selectively suppresses LPS-induced IL-6 transcription.”
- Also stated in: § Discussion · boosted
“In this report, we have shown that Pin1 selectively inhibits LPS-induced IL-6 transcription at the downstream of TLR4 in macrophages.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Interpretationreasoning
Pin1 controls macrophage maturation.
“These results suggest that Pin1 controls macrophage maturation.”
Quote in the paperSubstantial claim - Interpretationown data
Pin1 is activated by LPS stimulation.
“These results suggest that active type of Pin1 is increased by LPS stimulation.”
Quote in the paperSubstantial claim - Interpretationown data
Pin1 has a new function in the innate immune system.
“In this report, we have shown the Pin1's new function in innate immune system.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 8
- May combine two claims. 13
Classified as probably not a substantial claim.
PremisecitationPin1 regulates the functions of transcription factors NFAT, STAT3, and NF-κB that play important roles in the immune system.
“It has been reported that Pin1 regulates the functions of transcription factors, such as NFAT [2], STAT3 [3], and NF-κB [4] that play important roles in the immune system.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [2] Liu W Youn HD Zhou XZ Lu KP Liu JO 2001 Binding and regulation of the transcription factor NFAT by the peptidyl prolyl cis-trans isomerase Pin1. FEBS Letters 496 105 108 11356192 source
- cites [3] Lufei C Koh TH Uchida T Cao X 2007 Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity. Oncogene 26 7656 7664 17563747 source
- cites [4] Atkinson GP Nozell SE Harrison DK Stonecypher MS Chen D 2009 The prolyl isomerase Pin1 regulates the NF-kappaB signaling pathway and interleukin-8 expression in glioblastoma. Oncogene 28 3735 3745 19668231 PMC5987556 source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIκBNS inhibits IL-6 production selectively in macrophages and is induced by IL-10 and LPS.
“It has been reported that IκBNS that inhibits IL-6 production selectively in macrophages is induced by IL-10 and LPS [14].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [14] Hirotani T Lee PY Kuwata H Yamamoto M Matsumoto M 2005 The nuclear IkappaB protein IkappaBNS selectively inhibits lipopolysaccharide-induced IL-6 production in macrophages of the colonic lamina propria. J Immunol 174 3650 3657 15749903 source
May combine two claims.
Findingown dataWhole Pin1 and Pin1R68/69A (PPIase domain mutant) bound PU.1.
“Although whole Pin1 and PPIase domain mutant, Pin1R68/69A bound PU.1, WW domain mutant, Pin1W34A did not bind PU.1.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe median survival time of WT mice was 98.7±0.84 h and that of Pin1−/− mice was 59.8±12.4 h after LPS injection.
“The median survival time of WT mice was 98.7±0.84 h and that of Pin1−/− mice was 59.8±12.4 h after LPS injection (Table S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIL-6 mRNA level in macrophages from Pin1−/− mice is higher than that from WT mice after LPS injection, with the difference most significant at 4 h after LPS stimulation.
“On the other hands, the IL-6 mRNA level of the macrophages in the Pin1−/− mice was higher than that of WT mice after LPS-injection. The difference was the most significant at 4 h after LPS stimulation (Figure 3A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIL-6 serum levels increased 3-fold in WT and 10-fold in Pin1−/− mice 24 h after LPS injection.
“TNFα was increased 2.5- and 3-folds and IL-6 was increased 3- and 10-folds in WT and Pin1−/− mice respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTNFα serum levels increased 2.5-fold in WT and 3-fold in Pin1−/− mice 24 h after LPS injection.
“TNFα was increased 2.5- and 3-folds and IL-6 was increased 3- and 10-folds in WT and Pin1−/− mice respectively.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationPin1 specifically isomerizes phosphorylated serine or threonine residues preceding proline in certain proteins.
“The peptidyl prolyl cis/trans isomerase Pin1 specifically isomerizes phosphorylated serine or threonine residues preceding proline in certain proteins [1].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Takahashi K Uchida C Shin RW Shimazaki K Uchida T 2008 Prolyl isomerase Pin1: New findings on post-translational modifications and physiological substrates in cancer, Alzheimer's disease and asthma. Cell and Mol Life Sci 65 359 375 17965833 PMC11131890 source
May combine two claims.
Interpretationown dataPin1 controls the transcriptional activity of PU.1 and suppresses overreaction of macrophage that causes serious damages in lung.
“These results suggest that Pin1 controls the transcriptional activity of PU.1 and suppresses overreaction of macrophage that causes serious damages in lung.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationMassive activation of innate immunity caused by LPS leads to excess production of cytokines and development of septic shock or endotoxin shock syndrome.
“Massive activation of innate immunity caused by LPS leads to excess production of cytokines and other molecules, and development of septic shock or endotoxin shock syndrome, a fatal syndrome that is characterized by fever, hypotension, disseminated intravascular coagulation, and multiple organ failure [7].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Parrillo JE 1993 Pathogenetic mechanisms of septic shock. N Engl J Med 328 1471 1478 8479467 source
May combine two claims.
InterpretationcitationPin1 weakens LPS signal and corresponding inflammation.
“These results suggest that Pin1 weaken LPS signal and corresponding inflammation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenEach experiment was performed independently at least three times.
“Each experiment was performed independently at least three times, and the results of one representative experiment are shown.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationInflammation caused by LPS leads to the development of multiple organ failures in vivo.
“Inflammation caused by LPS leads to the development of multiple organ failures in vivo [7].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Parrillo JE 1993 Pathogenetic mechanisms of septic shock. N Engl J Med 328 1471 1478 8479467 source
May combine two claims.
PremisecitationMacrophages produce inflammatory cytokines TNFα and IL-6 in response to LPS stimulation, which causes serious damage in mice.
“Macrophages produce inflammatory cytokines, TNFα and IL-6 in response to LPS stimulation, which causes serious damage in mice [11].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Schletter J Heine H Ulmer AJ Rietschel ET 1995 Molecular mechanisms of endotoxin activity. Arch Microbiol 164 383 389 8588739 source
May combine two claims.
PremisecitationPin1 regulates degradation of inducible nitric oxide synthase and inhibits the production of LPS-induced nitric oxide in murine aortic endothelial cells (MAEC).
“Pin1 regulates degradation of inducible nitric oxide synthase and inhibits the production of LPS-induced nitric oxide in murine aortic endothelial cells (MAEC) [8].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Liu T Huang Y Likhotvorik RI Keshvara L Hoyt DG 2008 Protein Nerve in Mitosis Gene A Interacting-1 (Pin1) regulates degradation of inducible nitric oxide synthase in endothelial cells. Am J Physiol Cell Physiol 295 819 827 18650263 source
May combine two claims.
Interpretationown dataPin1 binds PU.1 in a cell and moves into a nucleus together.
“The results suggest that Pin1 binds PU.1 in a cell and moves into a nucleus together.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPin1 enhances the activity of transcription factors CREB and STAT3 in several cell types, which increase IL-10 production in macrophages.
“Pin1 enhances the activity of transcription factors, CREB and STAT3 in several cell types, which increase IL-10 production in macrophages [15], [16].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [15] Park P Huang H McMullen MR Bryan K Nagy LE 2008 Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in Raw 264.7 macrophages. J Leukoc Biol 83 1258 1266 18263767 source
- cites [16] Benkhart EM Siedlar M Wedel A Werner T Ziegler-Heitbrock HW 2000 Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression. J Immunol 165 1612 1617 10903771 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLPS is specifically recognized by TLR4.
“It is specifically recognized by TLR4 [6].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Poltorak A He X Smirnova I Liu MY Huffel CV 1998 Defective LPS signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutation in Tlr4 Gene. Science 28 2085 2088 9851930 source
Classified as probably not a substantial claim.
PremisecitationPhosphorylation of Ser16 of Pin1 impairs the function of Pin1.
“It has been reported previously that phoshorylation of Ser16 of Pin1 impairs the function of Pin1 [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Lu PJ Zhou XZ Liou YC Noel JP Lu KP 2002 Critical role of WW domain phosphorylation in regulating phosphoserine binding activity and Pin1 function. J Biol Chem 277 2381 2384 11723108 source
Cites
Pathogen Recognition and Innate Immunity
Akira, S., Uematsu, S., & Takeuchi, O. (2006) · Cell · doi:10.1016/j.cell.2006.02.015 · Cited by 11,974 · cited 1× · see citing works
“Each TLR specifically recognizes structural components of pathogens and triggers the innate immune response [5].”
BackgroundDefective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in <i>Tlr4</i> Gene
Poltorak, A., He, X., Smirnova, I., Liu, M.-Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998) · Science · doi:10.1126/science.282.5396.2085 · Cited by 7,631 · see citing works
Pathogenetic Mechanisms of Septic Shock
Epstein, F. H., & Parrillo, J. E. (1993) · New England Journal of Medicine · doi:10.1056/nejm199305203282008 · Cited by 1,548 · cited 2× · see citing works
“Inflammation caused by LPS leads to the development of multiple organ failures in vivo [7].”
BackgroundMolecular mechanisms of endotoxin activity
Schletter, J., Heine, H., Ulmer, A. J., & Rietschel, E. T. (1995) · Archives of Microbiology · doi:10.1007/bf02529735 · Cited by 308 · cited 1× · see citing works
“Pin1 selectively attenuated LPS-induced IL-6 transcription Macrophages produce inflammatory cytokines, TNFa and IL-6 in response to LPS stimulation, which causes serious damage in mice [11].”
BackgroundRole of Stat3 in Lipopolysaccharide-Induced IL-10 Gene Expression
Benkhart, E. M., Siedlar, M., Wedel, A., Werner, T., & Ziegler-Heitbrock, H. W. L. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.3.1612 · Cited by 249 · cited 1× · see citing works
“Pin1 enhances the activity of transcription factors, CREB and STAT3 in several cell types, which increase IL-10 production in macrophages [15,16].”
BackgroundLu, P.-J., Zhou, X. Z., Liou, Y.-C., Noel, J. P., & Lu, K. P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c100228200 · Cited by 244 · cited 1× · see citing works
“It has been reported previously that phoshorylation of Ser16 of Pin1 impairs the function of Pin1 [12].”
BackgroundUse of gelatin/plasma coated flasks for isolating human peripheral blood monocytes
Freundlich, B., & Avdalović, N. (1983) · Journal of Immunological Methods · doi:10.1016/0022-1759(83)90107-2 · Cited by 217 · see citing works
Mice Lacking Pin1 Develop Normally, but Are Defective in Entering Cell Cycle from G0 Arrest
Fujimori, F., Takahashi, K., Uchida, C., & Uchida, T. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1736 · Cited by 216 · cited 2× · see citing works
“In this study, we compared LPS-induced inflammatory damage between WT and Pin1 mice [10], and found that Pin1 plays a key role in suppressing LPS-induced PU.”
MethodSelf-citationPin1 and Par14 Peptidyl Prolyl Isomerase Inhibitors Block Cell Proliferation
Uchida, T., Takamiya, M., Takahashi, M., Miyashita, H., Ikeda, H., Terada, T., Matsuo, Y., Shirouzu, M., Yokoyama, S., Fujimori, F., et al. (2003) · Chemistry & Biology · doi:10.1016/s1074-5521(02)00310-1 · Cited by 175 · cited 4× · see citing works
“7pretreated with Pin1-specific inhibitor PiB [13].”
InfluentialSelf-citationHirotani, T., Lee, P. Y., Kuwata, H., Yamamoto, M., Matsumoto, M., Kawase, I., Akira, S., & Takeda, K. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.6.3650 · Cited by 167 · see citing works
Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity
Lufei, C., Koh, T. H., Uchida, T., & Cao, X. (2007) · Oncogene · doi:10.1038/sj.onc.1210567 · Cited by 106 · cited 3× · see citing works
“Taken together, we assume that Pin1 may up-regulate the production of IL-10 by accelerating the transcription activity of CREB/STAT3 and elevates the level of IL-6 specific IkBNS inhibitor in macrophages in response to LPS stimulation.”
BackgroundSelf-citationTakahashi, K., Uchida, C., Shin, R.-W., Shimazaki, K., & Uchida, T. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7270-0 · Cited by 105 · see citing works
Self-citationAtkinson, G. P., Nozell, S. E., Harrison, D. K., Stonecypher, M. S., Chen, D., & Benveniste, E. N. (2009) · Oncogene · doi:10.1038/onc.2009.232 · Cited by 75 · cited 1× · see citing works
“It has been reported that Pin1 regulates the functions of transcription factors, such as NFAT [2], STAT3 [3], and NF-kB [4] that play important roles in the immune system.”
BackgroundPin1 promotes production of Alzheimer’s amyloid β from β-cleaved amyloid precursor protein
Akiyama, H., Shin, R., Uchida, C., Kitamoto, T., & Uchida, T. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.08.130 · Cited by 62 · see citing works
Self-citationPark, P.-H., Huang, H., McMullen, M. R., Bryan, K., & Nagy, L. E. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0907631 · Cited by 53 · cited 1× · see citing works
“. Pin1 enhances the activity of transcription factors, CREB and STAT3 in several cell types, which increase IL-10 production in macrophages”
BackgroundLiu, W., Youn, H.-D., Zhou, X. Z., Lu, K. P., & Liu, J. O. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02411-5 · Cited by 52 · cited 1× · see citing works
“It has been reported that Pin1 regulates the functions of transcription factors, such as NFAT [2], STAT3 [3], and NF-kB [4] that play important roles in the immune system.”
BackgroundLiu, T., Huang, Y., Likhotvorik, R. I., Keshvara, L., & Hoyt, D. G. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00366.2007 · Cited by 25 · see citing works
Liu, T., Schneider, R. A., Shah, V., Huang, Y., Likhotvorik, R. I., Keshvara, L., & Hoyt, D. G. (2009) · Journal of Inflammation · doi:10.1186/1476-9255-6-20 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Li, X., Wang, H., Ding, J., Nie, S., Wang, L., Zhang, L., & Ren, S. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.10.043 · Cited by 69 · see citing works
Wang, H.-Y., Fu, J. C.-M., Lee, Y., & Lu, P. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00475-13 · Cited by 46 · see citing works
“have demonstrated that PIN1 protects mice from severe lipopolysaccharide-induced inflammation (16).”
BackgroundPin1 Regulates Osteoclast Fusion Through Suppression of the Master Regulator of Cell Fusion DC‐STAMP
Islam, R., Bae, H., Yoon, W., Woo, K. M., Baek, J., Kim, H., Uchida, T., & Ryoo, H. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24679 · Cited by 42 · see citing works
Self-citationPin1 Promotes NLRP3 Inflammasome Activation by Phosphorylation of p38 MAPK Pathway in Septic Shock
Dong, R., Xue, Z., Fan, G., Zhang, N., Wang, C., Li, G.-L., & Da, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.620238 · Cited by 34 · see citing works
“believe that Pin1 has a protective effect on LPS-induced shock (36).”
BackgroundMori, T., Hidaka, M., Lin, Y., et al. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.02.066 · Cited by 38 · see citing works
Self-citationRegulation of AU-Rich Element RNA Binding Proteins by Phosphorylation and the Prolyl Isomerase Pin1
Shen, Z.-J., & Malter, J. S. (2015) · Biomolecules · doi:10.3390/biom5020412 · Cited by 36 · see citing works
Krishnan, N., Titus, M. A., & Thapar, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085427 · Cited by 31 · see citing works
“The data is consistent with previous reports [55] that showed increased levels of inflammatory cytokines such as IL-6 in Pin1 2/2 mice (compared to wild type mice) in response to induction of inflammation by lipopolysaccharides.”
ResultPin1 promotes GR transactivation by enhancing recruitment to target genes
Poolman, T. M., Farrow, S. N., Matthews, L. C., Loudon, A. S. I., & Ray, D. W. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt624 · Cited by 20 · see citing works
“The phenotype of the Pin1 knockout mouse is complex, with premature aging, tauopathy and neurodegeneration [reviewed in (43,44)], insulin resistance (45) and also increased sensitivity to LPS challenge (46).”
BackgroundPin1, the Master Orchestrator of Bone Cell Differentiation
Islam, R., Yoon, W., & Ryoo, H. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25442 · Cited by 16 · see citing works
The Prolyl Isomerase Pin1 Modulates Development of CD8+ cDC in Mice
Barberi, T. J., Dunkle, A. D., He, Y.-W., Racioppi, L., & Means, A. R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029808 · Cited by 14 · see citing works
“1 (Figure 8C), as was previously reported in COS-7 cells [15].”
BackgroundResultInfluentialLee, Y. M., Teoh, D. E.-J., Yeung, K., & Liou, Y. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.956071 · Cited by 11 · see citing works
Pin1‐Mediated Prolyl Isomerization of Runx1 Affects PU.1 Expression in Pre‐Monocytes
Islam, R., Yoon, W.-J., Woo, K., Baek, J., & Ryoo, H. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24462 · Cited by 10 · see citing works
Molecular Mechanism of the Pin1–Histone H1 Interaction
Jinasena, D., Simmons, R. B., Gyamfi, H., & Fitzkee, N. C. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b01036 · Cited by 8 · see citing works
Huang, L., Mo, Z., Li, S., et al. (2018) · Medicine · doi:10.1097/md.0000000000012123 · Cited by 6 · see citing works
Liu, T., Schneider, R. A., Lee, N. Y., & Hoyt, D. G. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.089 · Cited by 2 · see citing works
Kouki, A., Souli, A., Bouabdallah, S., Ferjani, W., Dang, P. M., Ben‐Attia, M., & Benna, J. E. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.178025 · Cited by 2 · see citing works
Roles for Pin1 in Modulating Cells of the Innate Immune System
Barberi, T. J. (2011) · DukeSpace (Duke University)
- Authors
- Akiyama, H., Misawa, T., Ono, M., Uchida, C., & Uchida, T.
- Affiliations
- Tohoku University (JP)
- Corresponding author
- Uchida, Takafumi
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-02-04
- Volume
- 6
- Issue
- 2
- Pages
- e14656
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3033895
- OpenAlex
- W2059922312
- Cited by
- 17
- References
- 18
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 1 · 2018: 3 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 3 · 2012: 1
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Pin1, peptidyl-prolyl isomerase, endotoxic shock, lipopolysaccharide, innate immunity, lung inflammation, interleukin-6, PU.1
- MeSH terms
- NIMA-Interacting Peptidylprolyl Isomerase, Proto-Oncogene Protein Spi-1, Animals, Bacterial Infections, Cells, Cultured, Chlorocebus aethiops, Dose-Response Relationship, Drug, Endotoxins
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