IL-6 is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other tissue damage leading to inflammation. IL-6 also plays a role in fighting infection, as IL-6 has been shown in mice to be required for resistance against bacterium Streptococcus pneumoniae.
IL-6 is an important mediator of fever and of the acute phase response. It is capable of crossing the blood-brain barrier and initiating synthesis of PGE2 in the hypothalamus, thereby changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 stimulates energy mobilization that leads to increased body temperature. IL-6 can be secreted by macrophages in response to specific microbial molecules, referred to as pathogen-associated molecular patterns (PAMPs). These PAMPs bind to an important group of detection molecules of the innate immune system, called pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). These are present on the cell surface and intracellular compartments and induce intracellular signaling cascades that give rise to inflammatory cytokine production.
IL-6 is also essential for hybridoma growth and is found in many supplemental cloning media such as briclone. Inhibitors of IL-6 (including estrogen) are used to treat postmenopausal osteoporosis. IL-6 is also produced by adipocytes and is thought to be a reason why obese individuals have higher endogeneous levels of CRP. Intranasally administered IL-6 has been shown to improve sleep-associated consolidation of emotional memories.
IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells.
Role as myokine
IL-6 is also considered a myokine, a cytokine produced from muscle, and is elevated in response to muscle contraction. It is significantly elevated with exercise, and precedes the appearance of other cytokines in the circulation. During exercise, it is thought to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery.
IL-6 has extensive anti-inflammatory functions in its role as a myokine. IL-6 was the first myokine that was found to be secreted into the blood stream in response to muscle contractions. Aerobic exercise provokes a systemic cytokine response, including, for example, IL-6, IL-1 receptor antagonist (IL-1ra), and IL-10. IL-6 was serendipitously discovered as a myokine because of the observation that it increased in an exponential fashion proportional to the length of exercise and the amount of muscle mass engaged in the exercise. It has been consistently demonstrated that the plasma concentration of IL-6 increases during muscular exercise. This increase is followed by the appearance of IL-1ra and the anti-inflammatory cytokine IL-10. In general, the cytokine response to exercise and sepsis differs with regard to TNF-α. Thus, the cytokine response to exercise is not preceded by an increase in plasma-TNF-α. Following exercise, the basal plasma IL-6 concentration may increase up to 100-fold, but less dramatic increases are more frequent. The exercise-induced increase of plasma IL-6 occurs in an exponential manner and the peak IL-6 level is reached at the end of the exercise or shortly thereafter. It is the combination of mode, intensity, and duration of the exercise that determines the magnitude of the exercise-induced increase of plasma IL-6.
IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage. However, it has become evident that eccentric exercise is not associated with a larger increase in plasma IL-6 than exercise involving concentric “nondamaging” muscle contractions. This finding clearly demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.
Recent work has shown that both upstream and downstream signalling pathways for IL-6 differ markedly between myocytes and macrophages. It appears that unlike IL-6 signalling in macrophages, which is dependent upon activation of the NFκB signalling pathway, intramuscular IL-6 expression is regulated by a network of signalling cascades, including the Ca2+/NFAT and glycogen/p38 MAPK pathways. Thus, when IL-6 is signalling in monocytes or macrophages, it creates a pro-inflammatory response, whereas IL-6 activation and signalling in muscle is totally independent of a preceding TNF-response or NFκB activation, and is anti-inflammatory. 
IL-6, among an increasing number of other recently-identified myokines, thus remains an important topic in myokine research. It appears in muscle tissue and in the circulation during exercise at levels up to one hundred times basal rates, as noted, and is seen as having a beneficial impact on health and bodily functioning when elevated in response to physical exercise.
In addition to the membrane-bound receptor, a soluble form of IL-6R (sIL-6R) has been purified from human serum and urine. Many neuronal cells are unresponsive to stimulation by IL-6 alone, but differentiation and survival of neuronal cells can be mediated through the action of sIL-6R. The sIL-6R/IL-6 complex can stimulate neurites outgrowth and promote survival of neurons and, hence, may be important in nerve regeneration through remyelination.
IL-6 has been shown to lead to several neurological diseases through its impact on epigenetic modification within the brain. IL-6 activates the Phosphoinositide 3-kinase (PI3K) pathway, and a downstream target of this pathway is the protein kinase B (PKB) (Hodge et al., 2007). IL-6 activated PKB can phosphorylate the nuclear localization signal on DNA methyltransferase-1(DNMT1). This phosphorylation causes movement of DNMT1 to the nucleus, where it can be transcribed. DNMT1 recruits other DNMTs, including DNMT3A and DNMT3B, which, as a complex, recruit HDAC1. This complex adds methyl groups to CpG islands on gene promoters, repressing the chromatin structure surrounding the DNA sequence and inhibiting transcriptional machinery from accessing the gene to induce transcription. Increased IL-6, therefore, can hypermethylate DNA sequences and subsequently decrease gene expression through its effects on DNMT1 expression.
The induction of epigenetic modification by IL-6 has been proposed as a mechanism in the pathology of schizophrenia through the hypermethylation and repression of the GAD67 promoter. This hypermethylation may potentially lead to the decreased GAD67 levels seen in schizophrenic brains. GAD67 may be involved in the pathology of schizophrenia through its effect on GABA levels and on neural oscillations. Neural oscillations occur when inhibitory GABAergic neurons fire synchronously and cause inhibition of a multitude of target excitatory neurons at the same time, leading to a cycle of inhibition and disinhibition. These neural oscillations are impaired in schizophrenics, and these alterations may be responsible for both positive and negative symptoms of schizophrenia.
The epigenetic effects IL-6 have also been implicated in the pathology of depression. The effects of IL-6 on depression are mediated through the repression of brain-derived neurotrophic factor (BDNF) expression in the brain; DNMT1 hypermethylates the BDNF promoter and reduces BDNF levels. Altered BDNF function has been implicated in depression, which is likely due to epigenetic modification following IL-6 upregulation. BDNF is a neutrophic factor implicated in spine formation, density, and morphology on neurons. Downregulation of BDNF, therefore, may cause decreased connectivity in the brain. Depression is marked by altered connectivity, in particular between the anterior cingulate cortex and several other limbic areas, such as the hippocampus. The anterior cingulate cortex is responsible for detecting incongruences between expectation and perceived experience. Altered connectivity of the anterior cingulate cortex in depression, therefore, may cause altered emotions following certain experiences, leading to depressive reactions. This altered connectivity is mediated by IL-6 and its effect on epigenetic regulation of BDNF.
^Ferguson-Smith AC, Chen YF, Newman MS, May LT, Sehgal PB, Ruddle FH (April 1988). "Regional localization of the interferon-beta 2/B-cell stimulatory factor 2/hepatocyte stimulating factor gene to human chromosome 7p15-p21". Genomics2 (3): 203–208. doi:10.1016/0888-7543(88)90003-1. PMID3294161.Cite uses deprecated parameters (help)
^van der Poll T, Keogh CV, Guirao X, Buurman WA, Kopf M, Lowry SF (1997). "Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia". J Infect Dis176 (2): 439–444. doi:10.1086/514062. PMID9237710.
^Banks WA, Kastin AJ, Gutierrez EG (September 1994). "Penetration of interleukin-6 across the murine blood–brain barrier". Neurosci. Lett.179 (1–2): 53–6. doi:10.1016/0304-3940(94)90933-4. PMID7845624.Cite uses deprecated parameters (help)
^Bastard J, Jardel C, Delattre J, Hainque B et al. (1999). "Evidence for a Link Between Adipose Tissue Interleukin-6 Content and Serum C-Reactive Protein Concentrations in Obese Subjects". Circulation99 (16): 2219–2222. doi:10.1161/01.CIR.99.16.2219.c.
^Benedict C, Scheller J, Rose-John S, Born J, Marshall L (October 2009). "Enhancing influence of intranasal interleukin-6 on slow-wave activity and memory consolidation during sleep". FASEB J.23 (10): 3629–3636. doi:10.1096/fj.08-122853. PMID19546306.Cite uses deprecated parameters (help)
^The Role of Exercise-InducedMyokines in Muscle Homeostasis and the Defense against Chronic Diseases. Claus Brandt and Bente K. Pedersen. Journal of Biomedicine and Biotechnology. Volume 2010, Article ID 520258, 6 pages. doi:10.1155/2010/520258
^Muñoz-Cánoves P, Scheele C, Pedersen BK, Serrano AL (September 2013). "Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword?". FEBS J.280 (17): 4131–48. doi:10.1111/febs.12338. PMID23663276.Cite uses deprecated parameters (help)
^Schwantner A, Dingley AJ, Ozbek S, Rose-John S, Grötzinger J (January 2004). "Direct determination of the interleukin-6 binding epitope of the interleukin-6 receptor by NMR spectroscopy". J. Biol. Chem.279 (1): 571–576. doi:10.1074/jbc.M311019200. PMID14557255.Cite uses deprecated parameters (help)
^Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grötzinger J, Rose-John S, Kallen KJ (March 2003). "Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF". J. Biol. Chem.278 (11): 9528–9535. doi:10.1074/jbc.M210044200. PMID12643274.Cite uses deprecated parameters (help)
^Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T (August 1989). "Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130". Cell58 (3): 573–581. doi:10.1016/0092-8674(89)90438-8. PMID2788034.Cite uses deprecated parameters (help)
^Kallen KJ, zum Büschenfelde KH, Rose-John S (March 1997). "The therapeutic potential of interleukin-6 hyperagonists and antagonists". Expert Opin Investig Drugs6 (3): 237–266. doi:10.1517/135437126.96.36.199. PMID15989626.Cite uses deprecated parameters (help)
^Dubiński A, Zdrojewicz Z (April 2007). "[The role of interleukin-6 in development and progression of atherosclerosis]". Pol. Merkur. Lekarski (in Polish) 22 (130): 291–4. PMID17684929.Cite uses deprecated parameters (help)
^Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (March 2010). "A meta-analysis of cytokines in major depression". Biological Psychiatry67 (5): 446–457. doi:10.1016/j.biopsych.2009.09.033. PMID20015486.Cite uses deprecated parameters (help)
^Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (November 2010). "A meta-analysis of cytokines in Alzheimer's disease". Biological Psychiatry68 (10): 930–941. doi:10.1016/j.biopsych.2010.06.012. PMID20692646.Cite uses deprecated parameters (help)
^Hirohata S, Kikuchi H (dec 2012). "Changes in biomarkers focused on differences in disease course or treatment in patients with neuro-Behçet's disease.". Internal Medicine51 (24): 3359–65. doi:10.2169/internalmedicine.51.85834. PMID23257520.Cite uses deprecated parameters (help)
^Barton BE (August 2005). "Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes". Expert Opin. Ther. Targets9 (4): 737–752. doi:10.1517/14728188.8.131.527. PMID16083340.Cite uses deprecated parameters (help)
^Kaiser L, Fritz RS, Straus SE, Gubareva L, Hayden FG (July 2001). "Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses". J. Med. Virol.64 (3): 262–8. doi:10.1002/jmv.1045. PMID11424113.Cite uses deprecated parameters (help)
^ abForan E, Garrity-Park MM, Mureau C, Newell J, Smyrk TC, Limburg PJ, Egan LJ (April 2010). "Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6". Mol. Cancer Res.8 (4): 471–81. doi:10.1158/1541-7786.MCR-09-0496. PMID20354000.Cite uses deprecated parameters (help)
^ abHodge DR, Cho E, Copeland TD, Guszczynski T, Yang E, Seth AK, Farrar WL (2007). "IL-6 enhances the nuclear translocation of DNA cytosine-5-methyltransferase 1 (DNMT1) via phosphorylation of the nuclear localization sequence by the AKT kinase". Cancer Genomics Proteomics4 (6): 387–98. PMID18204201.
^Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E, DiGiorgi Gerevini V (November 2000). "Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study". Arch. Gen. Psychiatry57 (11): 1061–9. doi:10.1001/archpsyc.57.11.1061. PMID11074872.Cite uses deprecated parameters (help)
^Uhlhaas PJ, Singer W (February 2010). "Abnormal neural oscillations and synchrony in schizophrenia". Nat. Rev. Neurosci.11 (2): 100–13. doi:10.1038/nrn2774. PMID20087360.Cite uses deprecated parameters (help)
^ abcSharma RP, Tun N, Grayson DR (2008). "Depolarization induces downregulation of DNMT1 and DNMT3a in primary cortical cultures". Epigenetics3 (2): 74–80. doi:10.4161/epi.3.2.6103. PMID18536530.
^Hwang JP, Tsai SJ, Hong CJ, Yang CH, Lirng JF, Yang YM (December 2006). "The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression". Neurobiol. Aging27 (12): 1834–7. doi:10.1016/j.neurobiolaging.2005.10.013. PMID16343697.Cite uses deprecated parameters (help)
^ abSomerville LH, Heatherton TF, Kelley WM (August 2006). "Anterior cingulate cortex responds differentially to expectancy violation and social rejection". Nat. Neurosci.9 (8): 1007–8. doi:10.1038/nn1728. PMID16819523.Cite uses deprecated parameters (help)
De Kloet ER, Oitzl MS, Schöbitz B (1994). "Cytokines and the brain corticosteroid receptor balance: relevance to pathophysiology of neuroendocrine-immune communication". Psychoneuroendocrinology19 (2): 121–134. doi:10.1016/0306-4530(94)90002-7. PMID8190832.
Morishita R, Aoki M, Yo Y, Ogihara T (2003). "Hepatocyte growth factor as cardiovascular hormone: role of HGF in the pathogenesis of cardiovascular disease". Endocr. J.49 (3): 273–284. doi:10.1507/endocrj.49.273. PMID12201209.
Berger FG (2005). "The interleukin-6 gene: a susceptibility factor that may contribute to racial and ethnic disparities in breast cancer mortality". Breast Cancer Res. Treat.88 (3): 281–285. doi:10.1007/s10549-004-0726-0. PMID15609131.
Stenvinkel P, Ketteler M, Johnson RJ et al. (2005). "IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly". Kidney Int.67 (4): 1216–1233. doi:10.1111/j.1523-1755.2005.00200.x. PMID15780075.
Vgontzas AN, Bixler EO, Lin HM et al. (2005). "IL-6 and its circadian secretion in humans". Neuroimmunomodulation12 (3): 131–140. doi:10.1159/000084844. PMID15905620.
Jones SA (2005). "Directing transition from innate to acquired immunity: defining a role for IL-6". J. Immunol.175 (6): 3463–8. PMID16148087.