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 found in many supplemental cloning media such as briclone.
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.
When psychologically stressed, the human body produces stress hormones like cortisol, which are able to trigger interleukin-6 release into the circulation.
Role as myokine
IL-6 is also considered a myokine, a cytokine produced from muscle, which 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. IL-6 was the first myokine that was found to be secreted into the blood stream in response to muscle contractions.
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.
The first FDA approved anti-IL-6 treatment was for rheumatoid arthritis.
Anti-IL-6 therapy was initially developed for treatment of autoimmune diseases, but due to the role of IL-6 in chronic inflammation, IL-6 blockade was also evaluated for cancer treatment. IL-6 was seen to have roles in tumor microenvironment regulation, production of breast cancer stem cell-like cells, metastasis through down-regulation of E-cadherin, and alteration of DNA methylation in oral cancer.
Advanced/metastatic cancer patients have higher levels of IL-6 in their blood. One example of this is pancreatic cancer, with noted elevation of IL-6 present in patients correlating with poor survival rates.
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 the brains of people with schizophrenia. 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 schizophrenia, 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.
Additional preclinical and clinical data, suggest that Substance P [SP] and IL-6 may act in concert to promote major depression. SP, a hybrid neurotransmitter-cytokine, is co-transmitted with BDNF through paleo-spinothalamic circuitry from the periphery with collaterals into key areas of the limbic system. However, both IL6 and SP mitigate expression of BDNF in brain regions associated with negative affect and memory. SP and IL6 both relax tight junctions of the blood brain barrier, such that effects seen in fMRI experiments with these molecules may be a bidirectional mix of neuronal, glial, capillary, synaptic, paracrine, or endocrine-like effects. At the cellular level, SP is noted to increase expression of interleukin-6 (IL-6) through PI-3K, p42/44 and p38 MAP kinase pathways. Data suggest that nuclear translocation of NF-κB regulates IL-6 overexpression in SP-stimulated cells. This is of key interest as: 1) a meta-analysis indicates an association of major depressive disorder, C-reactive protein and IL6 plasma concentrations, 2) NK1R antagonists [five molecules] studied by 3 independent groups in over 2000 patients from 1998-2013 validate the mechanism as dose-related, fully effective antidepressant, with a unique safety profile.(see Summary of NK1RAs in Major Depression), 3) the preliminary observation that plasma concentrations of IL6 are elevated in depressed patients with cancer, and 4) selective NK1RAs may eliminate endogenous SP stress-induced augmentation of IL-6 secretion pre-clinically. These and many other reports suggest that a clinical study of a neutralizing IL-6 biological or drug based antagonist is likely warranted in patients with major depressive disorder, with or without co-morbid chronic inflammatory based illnesses; that the combination of NK1RAs and IL6 blockers may represent a new, potentially biomarkable approach to major depression, and possibly bipolar disorder.
Obesity is a known risk factor in the development of severe asthma. Recent data suggests that the inflammation associated with obesity, potentially mediated by the cytokine IL6, plays a role in causing poor lung function and increased risk for developing asthma exacerbations.
^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". Circulation. 99 (16): 2219–2222. doi:10.1161/01.CIR.99.16.2219.c (inactive 2019-08-18).
^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 Journal. 23 (10): 3629–36. doi:10.1096/fj.08-122853. PMID19546306.
^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
^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". The Journal of Biological Chemistry. 279 (1): 571–6. doi:10.1074/jbc.M311019200. PMID14557255.
^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". The Journal of Biological Chemistry. 278 (11): 9528–35. doi:10.1074/jbc.M210044200. PMID12643274.
^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". Cell. 58 (3): 573–81. doi:10.1016/0092-8674(89)90438-8. PMID2788034.
^Kallen KJ, zum Büschenfelde KH, Rose-John S (March 1997). "The therapeutic potential of interleukin-6 hyperagonists and antagonists". Expert Opinion on Investigational Drugs. 6 (3): 237–66. doi:10.1517/135437126.96.36.199. PMID15989626.
^Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (November 2010). "A meta-analysis of cytokines in Alzheimer's disease". Biological Psychiatry. 68 (10): 930–41. doi:10.1016/j.biopsych.2010.06.012. PMID20692646.
^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 Medicine. 51 (24): 3359–65. doi:10.2169/internalmedicine.51.8583. PMID23257520.
^Barton BE (August 2005). "Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes". Expert Opinion on Therapeutic Targets. 9 (4): 737–52. doi:10.1517/14728188.8.131.527. PMID16083340.
^Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, Nakano N, Ikeda Y, Sasaki T, Nishioka K, Hara M, Taguchi H, Kimura Y, Kato Y, Asaoku H, Kumagai S, Kodama F, Nakahara H, Hagihara K, Yoshizaki K, Kishimoto T (October 2005). "Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease". Blood. 106 (8): 2627–32. doi:10.1182/blood-2004-12-4602. PMID15998837.
^Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T (March 2008). "Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial". Lancet. 371 (9617): 998–1006. doi:10.1016/S0140-6736(08)60454-7. PMID18358927.
^Miao JW, Liu LJ, Huang J (July 2014). "Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma". International Journal of Oncology. 45 (1): 165–76. doi:10.3892/ijo.2014.2422. PMID24806843.
^Bellone G, Smirne C, Mauri FA, Tonel E, Carbone A, Buffolino A, Dughera L, Robecchi A, Pirisi M, Emanuelli G (June 2006). "Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: implications for survival". Cancer Immunology, Immunotherapy. 55 (6): 684–98. doi:10.1007/s00262-005-0047-0. PMID16094523.
^ 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 & Proteomics. 4 (6): 387–98. PMID18204201.
^Foran 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". Molecular Cancer Research. 8 (4): 471–81. doi:10.1158/1541-7786.MCR-09-0496. PMID20354000.
^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". Archives of General Psychiatry. 57 (11): 1061–9. doi:10.1001/archpsyc.57.11.1061. PMID11074872.
^Uhlhaas PJ, Singer W (February 2010). "Abnormal neural oscillations and synchrony in schizophrenia". Nature Reviews. Neuroscience. 11 (2): 100–13. doi:10.1038/nrn2774. PMID20087360.
^ abcSharma RP, Tun N, Grayson DR (2008). "Depolarization induces downregulation of DNMT1 and DNMT3a in primary cortical cultures". Epigenetics. 3 (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". Neurobiology of Aging. 27 (12): 1834–7. doi:10.1016/j.neurobiolaging.2005.10.013. PMID16343697.
^ abSomerville LH, Heatherton TF, Kelley WM (August 2006). "Anterior cingulate cortex responds differentially to expectancy violation and social rejection". Nature Neuroscience. 9 (8): 1007–8. doi:10.1038/nn1728. PMID16819523.
^Azzolina A, Bongiovanni A, Lampiasi N (December 2003). "Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells". Biochimica et Biophysica Acta. 1643 (1–3): 75–83. doi:10.1016/j.bbamcr.2003.09.003. PMID14654230.
^Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M (May 2013). "Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies". Journal of Psychopharmacology. 27 (5): 424–34. doi:10.1177/0269881113480990. PMID23539641.
^Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NM (September 1998). "Distinct mechanism for antidepressant activity by blockade of central substance P receptors". Science. 281 (5383): 1640–5. doi:10.1126/science.281.5383.1640. PMID9733503.
^Musselman DL, Miller AH, Porter MR, Manatunga A, Gao F, Penna S, Pearce BD, Landry J, Glover S, McDaniel JS, Nemeroff CB (August 2001). "Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings". The American Journal of Psychiatry. 158 (8): 1252–7. doi:10.1176/appi.ajp.158.8.1252. PMID11481159.
^Zhu GF, Chancellor-Freeland C, Berman AS, Kage R, Leeman SE, Beller DI, Black PH (June 1996). "Endogenous substance P mediates cold water stress-induced increase in interleukin-6 secretion from peritoneal macrophages". The Journal of Neuroscience. 16 (11): 3745–52. doi:10.1523/JNEUROSCI.16-11-03745.1996. PMID8642417.
^Clinical trial number NCT02473289 for "An Efficacy and Safety Study of Sirukumab in Participants With Major Depressive Disorder." at ClinicalTrials.gov
De Kloet ER, Oitzl MS, Schöbitz B (1994). "Cytokines and the brain corticosteroid receptor balance: relevance to pathophysiology of neuroendocrine-immune communication". Psychoneuroendocrinology. 19 (2): 121–34. doi:10.1016/0306-4530(94)90002-7. PMID8190832.
Morishita R, Aoki M, Yo Y, Ogihara T (June 2002). "Hepatocyte growth factor as cardiovascular hormone: role of HGF in the pathogenesis of cardiovascular disease". Endocrine Journal. 49 (3): 273–84. doi:10.1507/endocrj.49.273. PMID12201209.
Culig Z, Bartsch G, Hobisch A (November 2002). "Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth". Molecular and Cellular Endocrinology. 197 (1–2): 231–8. doi:10.1016/S0303-7207(02)00263-0. PMID12431817.
Rattazzi M, Puato M, Faggin E, Bertipaglia B, Zambon A, Pauletto P (October 2003). "C-reactive protein and interleukin-6 in vascular disease: culprits or passive bystanders?". Journal of Hypertension. 21 (10): 1787–803. doi:10.1097/00004872-200310000-00002. PMID14508181.
Berger FG (December 2004). "The interleukin-6 gene: a susceptibility factor that may contribute to racial and ethnic disparities in breast cancer mortality". Breast Cancer Research and Treatment. 88 (3): 281–5. doi:10.1007/s10549-004-0726-0. PMID15609131.
Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits-Filho R, Riella M, Heimbürger O, Cederholm T, Girndt M (April 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 International. 67 (4): 1216–33. doi:10.1111/j.1523-1755.2005.00200.x. PMID15780075.
Vgontzas AN, Bixler EO, Lin HM, Prolo P, Trakada G, Chrousos GP (2005). "IL-6 and its circadian secretion in humans". Neuroimmunomodulation. 12 (3): 131–40. doi:10.1159/000084844. PMID15905620.
Mastorakos G, Ilias I (November 2006). "Interleukin-6: a cytokine and/or a major modulator of the response to somatic stress". Annals of the New York Academy of Sciences. 1088: 373–81. doi:10.1196/annals.1366.021. PMID17192581.