Cited by 117Tryptophan and brain disordersGenetic Associations and EpidemiologyStress Responses and Cortisol

The DOI matches its Crossref record; 90 of the 90 references it cites were found in a registry or an index.

Depression and interleukin-6 signaling: A Mendelian Randomization study

Open access

Kelly, Kristen M., Smith, Jennifer A., Mezuk, Briana·2021·Brain, Behavior, and Immunity

DOI 10.1016/j.bbi.2021.02.019PMC PMC11081733

Open this paper in CoChat — free account Open PDF

Abstract

BACKGROUND: A large body of research has reported associations between depression and elevated interleukin-6 (IL-6), a cytokine with several roles including pro-inflammatory signaling. The nature and directionality of this relationship are not yet clear. In this study we use Mendelian Randomization to examine the possibility of a causal relationship between IL-6 and depressive symptoms, and to explore multiple signaling pathways that could serve as mechanisms for this relationship. METHODS: This study uses a two-sample Mendelian Randomization design. Data come from the UK Biobank (n = 89,119) and published summary statistics from six existing GWAS analyses. The primary analysis focuses on the soluble interleukin-6 receptor (sIL-6R), which is involved in multiple signaling pathways. Exploratory analyses use C-reactive protein (CRP) and soluble glycoprotein 130 (sgp130) to further examine potential underlying mechanisms. RESULTS: Results are consistent with a causal effect of sIL-6R on depression (PCA-IVW Odds Ratio: 1.023 (95% Confidence Interval: 1.006-1.039), p = 0.006). Exploratory analyses demonstrate that the relationship could be consistent with either decreased classical signaling or increased trans signaling as the underlying mechanism. DISCUSSION: These results strengthen the body evidence implicating IL-6 signaling in depression. When compared with existing observational and animal findings, the direction of these results suggests involvement of IL-6 trans signaling. Further study is needed to examine whether IL6R genetic variants might influence IL-6 trans signaling in the brain, as well as to explore other potential pathways linking depression and inflammation.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1016/j.bbi.2021.02.019

Cites

90 of 90 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression
Bowden, J., Davey Smith, G., & Burgess, S. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv080 · Cited by 9,816
The UK Biobank resource with deep phenotyping and genomic data
Bycroft, C., Freeman, C., Petkova, D., Band, G., Elliott, L. T., Sharp, K., Motyer, A., Vukcevic, D., Delaneau, O., O’Connell, J., et al. (2018) · Nature · doi:10.1038/s41586-018-0579-z · Cited by 8,876
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,525
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395
Mendelian randomization: genetic anchors for causal inference in epidemiological studies
Davey Smith, G., & Hemani, G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu328 · Cited by 4,677
Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology
Lawlor, D. A., Harbord, R. M., Sterne, J. A. C., Timpson, N., & Davey Smith, G. (2008) · Statistics in Medicine · doi:10.1002/sim.3034 · Cited by 4,618
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., et al. (2003) · Science · doi:10.1126/science.1083328 · Cited by 4,321
Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression
Miller, A. H., Maletic, V., & Raison, C. L. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.11.029 · Cited by 3,848
The pro- and anti-inflammatory properties of the cytokine interleukin-6
Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.034 · Cited by 3,212
Cytokines sing the blues: inflammation and the pathogenesis of depression
Raison, C. L., Capuron, L., & Miller, A. H. (2006) · Trends in Immunology · doi:10.1016/j.it.2005.11.006 · Cited by 3,009
Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression
eQTLGen, Wray, N. R., 23andMe, the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E. M., Abdellaoui, A., Adams, M. J., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0090-3 · Cited by 3,005
Inflammatory Blockade Restores Adult Hippocampal Neurogenesis
Monje, M. L., Toda, H., & Palmer, T. D. (2003) · Science · doi:10.1126/science.1088417 · Cited by 2,426
Genomic atlas of the human plasma proteome
Sun, B. B., Maranville, J. C., Peters, J. E., Stacey, D., Staley, J. R., Blackshaw, J., Burgess, S., Jiang, T., Paige, E., Surendran, P., et al. (2018) · Nature · doi:10.1038/s41586-018-0175-2 · Cited by 2,268
Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors
EPIC- InterAct Consortium, Burgess, S., Scott, R. A., Timpson, N. J., Davey Smith, G., & Thompson, S. G. (2015) · European Journal of Epidemiology · doi:10.1007/s10654-015-0011-z · Cited by 1,803
A review of instrumental variable estimators for Mendelian randomization
Burgess, S., Small, D. S., & Thompson, S. G. (2015) · Statistical Methods in Medical Research · doi:10.1177/0962280215597579 · Cited by 1,769
A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression.
Goldsmith, D. R., Rapaport, M. H., & Miller, B. J. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.3 · Cited by 1,683
Bias due to participant overlap in two‐sample Mendelian randomization
Burgess, S., Davies, N. M., & Thompson, S. G. (2016) · Genetic Epidemiology · doi:10.1002/gepi.21998 · Cited by 1,624
Peripheral cytokine and chemokine alterations in depression: a meta‐analysis of 82 studies
Köhler, C. A., Freitas, T. H., Maes, M., de Andrade, N. Q., Liu, C. S., Fernandes, B. S., Stubbs, B., Solmi, M., Veronese, N., Herrmann, N., et al. (2017) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12698 · Cited by 1,443
Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators.
Pierce, B. L., & Burgess, S. (2013) · American Journal of Epidemiology · doi:10.1093/aje/kwt084 · Cited by 1,389
Cytokine Mechanisms of Central Sensitization: Distinct and Overlapping Role of Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor-α in Regulating Synaptic and Neuronal Activity in the Superficial Spinal Cord
Kawasaki, Y., Zhang, L., Cheng, J.-K., & Ji, R.-R. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3338-07.2008 · Cited by 1,162
The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
(2012) · The Lancet · doi:10.1016/s0140-6736(12)60110-x · Cited by 1,146
Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder
Haapakoski, R., Mathieu, J., Ebmeier, K. P., Alenius, H., & Kivimäki, M. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.06.001 · Cited by 1,129
Triangulation in aetiological epidemiology
Lawlor, D. A., Tilling, K., & Davey Smith, G. (2017) · International Journal of Epidemiology · doi:10.1093/ije/dyw314 · Cited by 1,129
Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge
Shemer, A., Grozovski, J., Tay, T. L., Tao, J., Volaski, A., Süß, P., Ardura-Fabregat, A., Gross-Vered, M., Kim, J.-S., David, E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07548-5 · Cited by 1,052
Causal associations between risk factors and common diseases inferred from GWAS summary data
Zhu, Z., Zheng, Z., Zhang, F., Wu, Y., Trzaskowski, M., Maier, R., Robinson, M. R., McGrath, J. J., Visscher, P. M., Wray, N. R., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02317-2 · Cited by 951
IL-6 and Its Soluble Receptor Orchestrate a Temporal Switch in the Pattern of Leukocyte Recruitment Seen during Acute Inflammation
Hurst, S. M., Wilkinson, T. S., McLoughlin, R. M., Jones, S., Horiuchi, S., Yamamoto, N., Rose-John, S., Fuller, G. M., Topley, N., & Jones, S. A. (2001) · Immunity · doi:10.1016/s1074-7613(01)00151-0 · Cited by 811
Commentary: Two-sample Mendelian randomization: opportunities and challenges
Lawlor, D. A. (2016) · International Journal of Epidemiology · doi:10.1093/ije/dyw127 · Cited by 810
Connecting genetic risk to disease end points through the human blood plasma proteome
Suhre, K., Arnold, M., Bhagwat, A. M., Cotton, R. J., Engelke, R., Raffler, J., Sarwath, H., Thareja, G., Wahl, A., DeLisle, R. K., et al. (2017) · Nature Communications · doi:10.1038/ncomms14357 · Cited by 800
Cytokine, Sickness Behavior, and Depression
Dantzer, R. (2009) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2009.02.002 · Cited by 789
On measures of gametic disequilibrium.
Lewontin, R. C. (1988) · Genetics · doi:10.1093/genetics/120.3.849 · Cited by 712
Interleukin-6 and its receptors: a highly regulated and dynamic system
Wolf, J., Rose-John, S., & Garbers, C. (2014) · Cytokine · doi:10.1016/j.cyto.2014.05.024 · Cited by 618
Reduced Hippocampal Neurogenesis in Adult Transgenic Mice with Chronic Astrocytic Production of Interleukin-6
Vallières, L., Campbell, I. L., Gage, F. H., & Sawchenko, P. E. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-02-00486.2002 · Cited by 608
Best (but oft-forgotten) practices: the design, analysis, and interpretation of Mendelian randomization studies
Haycock, P., Burgess, S., Wade, K. H., Bowden, J., Relton, C. L., & Smith, G. D. (2016) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.115.118216 · Cited by 595
IL-1β, IL-6, TNF- α and CRP in Elderly Patients with Depression or Alzheimer’s Disease: Systematic Review and Meta-Analysis
Ng, A., Tam, W. W., Zhang, M. W., Ho, C. S., Husain, S. F., McIntyre, R. S., & Ho, R. C. (2018) · Scientific Reports · doi:10.1038/s41598-018-30487-6 · Cited by 572
Interleukin-6: Biology, signaling and strategies of blockade
Schaper, F., & Rose‐John, S. (2015) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2015.07.004 · Cited by 531
The role of interleukin-6 signaling in nervous tissue
Rothaug, M., Becker-Pauly, C., & Rose-John, S. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.03.018 · Cited by 491
Interleukin-6: A Masterplayer in the Cytokine Network
Uciechowski, P., & Dempke, W. C. M. (2020) · Oncology · doi:10.1159/000505099 · Cited by 484
Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease
Yao, C., Chen, G., Song, C., Keefe, J., Mendelson, M., Huan, T., Sun, B. B., Laser, A., Maranville, J. C., Wu, H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05512-x · Cited by 431
Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells
Heink, S., Yogev, N., Garbers, C., Herwerth, M., Aly, L., Gasperi, C., Husterer, V., Croxford, A. L., Möller-Hackbarth, K., Bartsch, H. S., et al. (2017) · Nature Immunology · doi:10.1038/ni.3632 · Cited by 386
Acute Effects of Recombinant Human Interleukin-6 on Endocrine and Central Nervous Sleep Functions in Healthy Men
Späth‐Schwalbe, E. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.83.5.1573 · Cited by 377
Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
Folkersen, L., Fauman, E., Sabater-Lleal, M., Strawbridge, R. J., Frånberg, M., Sennblad, B., Baldassarre, D., Veglia, F., Humphries, S. E., Rauramaa, R., et al. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006706 · Cited by 343
Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases
Ferreira, R. C., Freitag, D. F., Cutler, A. J., Howson, J. M. M., Rainbow, D. B., Smyth, D. J., Kaptoge, S., Clarke, P., Boreham, C., Coulson, R. M., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003444 · Cited by 316
Interleukin-6 and its receptor: from bench to bedside
Scheller, J., & Rose‐John, S. (2006) · Medical Microbiology and Immunology · doi:10.1007/s00430-006-0019-9 · Cited by 299
Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort
Khandaker, G. M., Zuber, V., Rees, J. M. B., Carvalho, L. A., Mason, A. M., Foley, C. N., Gkatzionis, A., Jones, P. B., & Burgess, S. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0395-3 · Cited by 287
The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6.
Peters, M. J., Jacobs, S., Ehlers, M., Vollmer, P., Müllberg, J., Wolf, E., Brem, G., Büschenfelde, K. H. M. Z., & Rose‐John, S. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.4.1399 · Cited by 276
Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms
Kappelmann, N., Arloth, J., Georgakis, M. K., Czamara, D., Rost, N., Ligthart, S., Khandaker, G. M., & Binder, E. B. (2020) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2020.3436 · Cited by 270
Sensitization of unmyelinated sensory fibers of the joint nerve to mechanical stimuli by interleukin‐6 in the rat: An inflammatory mechanism of joint pain
Brenn, D., Richter, F., & Schaible, H. (2006) · Arthritis & Rheumatism · doi:10.1002/art.22282 · Cited by 252
Trans-Signaling Is a Dominant Mechanism for the Pathogenic Actions of Interleukin-6 in the Brain
Campbell, I. L., Erta, M., Lim, S. L., Frausto, R. F., May, U., Rose‐John, S., Scheller, J., & Hidalgo, J. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2830-13.2014 · Cited by 247
IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors
Chourbaji, S., Urani, A., Inta, I., Sanchis-Segura, C., Brandwein, C., Zink, M., Schwaninger, M., & Gass, P. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.05.001 · Cited by 241
The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling
Baran, P., Hansen, S., Waetzig, G. H., Akbarzadeh, M., Lamertz, L., Huber, H. J., Ahmadian, M. R., Moll, J. M., & Scheller, J. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001163 · Cited by 235
The Impact of Phenotypic and Genetic Heterogeneity on Results of Genome Wide Association Studies of Complex Diseases
Manchia, M., Cullis, J., Turecki, G., Rouleau, G. A., Uher, R., & Alda, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076295 · Cited by 207
Mathematical properties of the measure of linkage disequilibrium
Canzoniero, J. V., & Rosenberg, N. A. (2008) · Theoretical Population Biology · doi:10.1016/j.tpb.2008.05.006 · Cited by 207
Increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and those with major depressive disorder
Sasayama, D., Hattori, K., Wakabayashi, C., Teraishi, T., Hori, H., Ota, M., Yoshida, S., Arima, K., Higuchi, T., Amano, N., et al. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2012.12.001 · Cited by 198
The association between C-reactive protein, Interleukin-6 and depression among older adults in the community: A systematic review and meta-analysis
Smith, K. J., Au, B., Ollis, L., & Schmitz, N. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.12.005 · Cited by 197
Mendelian randomization with fine‐mapped genetic data: Choosing from large numbers of correlated instrumental variables
Burgess, S., Zuber, V., Valdés‐Márquez, E., Sun, B. B., & Hopewell, J. C. (2017) · Genetic Epidemiology · doi:10.1002/gepi.22077 · Cited by 196
Depressive Symptoms, Health Behaviors, and Subsequent Inflammation in Patients With Coronary Heart Disease: Prospective Findings From the Heart and Soul Study
Duivis, H. E., de Jonge, P., Penninx, B. W., Na, B. Y., Cohen, B. E., & Whooley, M. A. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.10081163 · Cited by 191
Hippocampal neuroplasticity in major depressive disorder
Malykhin, N. V., & Coupland, N. J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.04.047 · Cited by 189
Association of socioeconomic status with inflammation markers in Black and White men and women in the Coronary Artery Risk Development in Young Adults (CARDIA) study
Gruenewald, T. L., Cohen, S., Matthews, K. A., Tracy, R., & Seeman, T. E. (2009) · Social Science & Medicine · doi:10.1016/j.socscimed.2009.05.018 · Cited by 188
Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut–microbiota–brain axis
Zhang, J.-C., Yao, W., Dong, C., Yang, C., Ren, Q., Ma, M., & Hashimoto, K. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.112 · Cited by 182
The soluble interleukin 6 receptor: advanced therapeutic options in inflammation
Rose‐John, S. (2017) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.782 · Cited by 169
The concept of residual confounding in regression models and some applications
Becher, H. (1992) · Statistics in Medicine · doi:10.1002/sim.4780111308 · Cited by 168
Reviewing the genetics of heterogeneity in depression: operationalizations, manifestations and etiologies
Cai, N., Choi, K. W., & Fried, E. I. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa115 · Cited by 160
Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior
Harden, L. M., du Plessis, I., Poole, S., & Laburn, H. P. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.05.016 · Cited by 159
IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling
Hoge, J., Yan, I., Jänner, N., Schumacher, V., Chalaris, A., Steinmetz, O. M., Engel, D. R., Scheller, J., Rose‐John, S., & Mittrücker, H. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201044 · Cited by 158
Acute Effects of Recombinant Human Interleukin-6 on Endocrine and Central Nervous Sleep Functions in Healthy Men1
Späth‐Schwalbe, E., Hansen, K., Schmidt, F., Schrezenmeier, H., Marshall, L., Burger, K., Fehm, H. L., & Jan Born, A. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.5.4795 · Cited by 157
Multiple Sklerose: Neu entdeckter Signalmechanismus macht T-Zellen pathogen
(2017) · Fortschritte der Neurologie · Psychiatrie · doi:10.1055/s-0042-123476 · Cited by 156
The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases
Garbers, C., Monhasery, N., Aparicio-Siegmund, S., Lokau, J., Baran, P., Nowell, M. A., Jones, S. A., Rose-John, S., & Scheller, J. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.05.018 · Cited by 155
Signaling of Human Ciliary Neurotrophic Factor (CNTF) Revisited
Schuster, B., Kovaleva, M., Sun, Y. E., Regenhard, P., Matthews, V. B., Grötzinger, J., Rose‐John, S., & Kallen, K. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210044200 · Cited by 142
Neural activities of IL‐6‐type cytokines often depend on soluble cytokine receptors
März, P., Otten, U., & Rose-John, S. (1999) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1999.00755.x · Cited by 142
Targeting classical IL-6 signalling or IL-6 trans-signalling in depression?
Maes, M., Anderson, G., Kubera, M., & Berk, M. (2014) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.888417 · Cited by 140
Correction: Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort
Khandaker, G. M., Zuber, V., Rees, J. M. B., Carvalho, L. A., Mason, A. M., Foley, C. N., Gkatzionis, A., Jones, P. B., & Burgess, S. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0857-7 · Cited by 139
Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration
Lehtimäki, K. A., Keränen, T., Huhtala, H., Hurme, M., Ollikainen, J., Honkaniemi, J., Palmio, J., & Peltola, J. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.01.024 · Cited by 131
Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior
Burton, M. D., Sparkman, N. L., & Johnson, R. W. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-54 · Cited by 128
Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms
Engler, H., Brendt, P., Wischermann, J., Wegner, A., Rohling, R., Schoemberg, T., Meyer, U., Gold, R., Peters, J., Benson, S., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.264 · Cited by 127
Genome-wide association study of CSF levels of 59 Alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation
Kauwe, J. S. K., Bailey, M. H., Ridge, P. G., Perry, R., Wadsworth, M. E., Hoyt, K. L., Staley, L. A., Karch, C. M., Harari, O., Cruchaga, C., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004758 · Cited by 125
The genetics of depression: successful genome-wide association studies introduce new challenges
Ormel, J., Hartman, C. A., & Snieder, H. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0450-5 · Cited by 120
Using the MR-Base platform to investigate risk factors and drug targets for thousands of phenotypes
Walker, V. M., Davies, N. M., Hemani, G., Zheng, J., Haycock, P., Gaunt, T. R., Smith, G. D., & Martin, R. M. (2019) · Wellcome Open Research · doi:10.12688/wellcomeopenres.15334.1 · Cited by 113
The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman’s disease
Sun, Y., Wang, D., Salvadore, G., Hsu, B., Curran, M., Casper, C., Vermeulen, J., Kent, J. M., Singh, J., Drevets, W. C., et al. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2017.06.014 · Cited by 100
Higher CSF Interleukin-6 and CSF Interleukin-8 in Current Depression in Older Women. Results from a Population-Based Sample
Kern, S., Skoog, I., Börjesson-Hanson, A., Blennow, K., Zetterberg, H., Östling, S., Kern, J., Gudmundsson, P., Marlow, T., Rosengren, L., et al. (2014) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2014.05.006 · Cited by 94
CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis1Part of this work was presented in abstract form at the Twenty-Seventh Annual Meeting of the Society for Neuroscience, October 25–30, 1997, New Orleans, LA, USA.1
Padberg, F., Feneberg, W. W., Schmidt, S., Schwarz, M., Körschenhausen, D. A., Greenberg, B. D., Nolde, T., Müller, N., Trapmann, H., König, N., et al. (1999) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(99)00120-4 · Cited by 88
Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice
Burton, M. D., Rytych, J. L., Freund, G. G., & Johnson, R. W. (2013) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.01.002 · Cited by 73
Connecting genetic risk to disease endpoints through the human blood plasma proteomePreprint
Suhre, K., Arnold, M., Bhagwat, A. M., et al. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/086793 · Cited by 64
The impact of tocilizumab on anxiety and depression in patients with rheumatoid arthritis
Tiosano, S., Yavne, Y., Watad, ‬., Langevitz, P., Lidar, M., Feld, J., Tishler, M., Aamar, S., Elkayam, O., Balbir‐Gurman, A., et al. (2020) · European Journal of Clinical Investigation · doi:10.1111/eci.13268 · Cited by 57
Do cytokines really sing the blues?
Raison, C. L., & Miller, A. H. (2013) · Europe PMC (PubMed Central) · Cited by 52
Entzündung und Depression
(2017) · Fortschritte der Neurologie · Psychiatrie · doi:10.1055/s-0043-104029 · Cited by 50
The Contribution of the Functional IL6R Polymorphism rs2228145, eQTLs and Other Genome-Wide SNPs to the Heritability of Plasma sIL-6R Levels
Collaborators, A., van Dongen, J., Jansen, R., Smit, D. J. A., Hottenga, J., Mbarek, H., Willemsen, G. A. H. M., Kluft, C., Penninx, B. W. J. H., Ferreira, M. A. R., et al. (2014) · Behavior Genetics · doi:10.1007/s10519-014-9656-8 · Cited by 45
Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome
Sasayama, D., Hattori, K., Ogawa, S., Yokota, Y., Matsumura, R., Teraishi, T., Hori, H., Ota, M., Yoshida, S., & Kunugi, H. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw366 · Cited by 43
Involvement of Spinal IL-6 Trans-Signaling in the Induction of Hyperexcitability of Deep Dorsal Horn Neurons by Spinal Tumor Necrosis Factor-Alpha
König, C., Morch, E., Eitner, A., Möller, C., Turnquist, B. P., Schaible, H., & Ebersberger, A. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4159-15.2016 · Cited by 43
Randomised by (your) god: robust inference from an observational study design
Smith, G. D. (2006) · Journal of Epidemiology & Community Health · doi:10.1136/jech.2004.031880 · Cited by 39
Constraints on eQTL Fine Mapping in the Presence of Multisite Local Regulation of Gene Expression
Zeng, B., Lloyd‐Jones, L. R., Holloway, A., Marigorta, U. M., Metspalu, A., Montgomery, G. W., Esko, T., Brigham, K. L., Quyyumi, A. A., Idaghdour, Y., et al. (2017) · G3 Genes Genomes Genetics · doi:10.1534/g3.117.043752 · Cited by 26

Sorted by citations

Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts
Milaneschi, Y., Kappelmann, N., Ye, Z., Lamers, F., Moser, S., Jones, P. B., Burgess, S., Penninx, B. W. J. H., & Khandaker, G. M. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01188-w · Cited by 385
“Similar divergent MR results have also been reported for schizophrenia and depression, suggesting a protective effect of CRP and a riskincreasing effect of soluble IL-6 receptor (IL-6R) on schizophrenia and depression risk, respectively [45, 46].”
Result
Selected biomarkers of depression: what are the effects of cytokines and inflammation
Harsanyi, S., Kupcova, I., Danisovic, L., & Klein, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010578 · Cited by 299
“In addition to increased IL-6 levels, sIL-R6 levels were reported in depressed patients, with elevated levels of both persisting even after the start of antidepressant treatment [87,88].”
Background
New insights from the last decade of research in psychiatric genetics: discoveries, challenges and clinical implications
Andreassen, O. A., Hindley, G., Frei, O., & Smeland, O. B. (2023) · World Psychiatry · doi:10.1002/wps.21034 · Cited by 275
Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study
Hamilton, F., Thomas, M., Arnold, D., Palmer, T., Moran, E., Mentzer, A. J., Maskell, N. A., Baillie, J. K., Summers, C., Hingorani, A. D., et al. (2023) · PLoS Medicine · doi:10.1371/journal.pmed.1004174 · Cited by 144
“We did not identify a robust effect on sepsis when instrumenting gp130, although there is much less evidence that genetic variation at this locus affects IL-6 signalling [45].”
Background
Role of inflammation in depression and anxiety: Tests for disorder specificity, linearity and potential causality of association in the UK Biobank
Ye, Z., Kappelmann, N., Moser, S., Smith, G. D., Burgess, S., Jones, P. B., & Khandaker, G. M. (2021) · EClinicalMedicine · doi:10.1016/j.eclinm.2021.100992 · Cited by 105
“Taken together, these findings also align with a recent MR study on the effects of genetically predicted sIL-6R, sgp130 (an inhibitor of IL-6 trans-signalling [51]), and CRP on recurrent depression, which suggested that increased IL-6 trans-signalling or decreased IL-6 classic signalling could be responsible for a ris…”
BackgroundResult

See all 117

Authors: Kelly, K. M., Smith, J. A., & Mezuk, B.
Affiliations: University of Michigan (US)
Corresponding author: Kelly, Kristen M.
ORCID: Kelly, Kristen M.
Smith, Jennifer A.
Mezuk, Briana
Venue: Brain, Behavior, and Immunity
Publisher: Elsevier BV
Published: 2021-07
Volume: 95
Pages: 106-114
ISSN: 0889-1591 (ISSN-L)
DOI: 10.1016/j.bbi.2021.02.019
PMC: PMC11081733
OpenAlex: W3132094446
Cited by: 117
References: 90
Citations by year: 2026: 23 · 2025: 22 · 2024: 34 · 2023: 20 · 2022: 15 · 2021: 3
FWCI: 5.97
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Brain Behavior and Immunity (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
VU Research Portal (publishedVersion, other-oa)
PubMed Central (acceptedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders: National Institute of Mental Health (K01-MH093642-A1, 41812)
University of Michigan (T32-HG00040)
National Institutes of Health
National Human Genome Research Institute (T32-HG00040)
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: depression, interleukin-6, IL-6 signaling, soluble IL-6 receptor, trans-signaling, C-reactive protein, soluble glycoprotein 130, inflammation, causal relationship, genetic variants
MeSH terms: Animals, Depression, Interleukin-6, Receptors, Interleukin-6, Cytokine Receptor gp130, Mendelian Randomization Analysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Depression and interleukin-6 signaling: A Mendelian Randomization study

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks