Interleukin 6


Interleukin 6
Interleukin 6 (interferon, beta 2)

PDB rendering based on 1ALU.
Identifiers
Symbols IL6; BSF2; HGF; HSF; IFNB2; IL-6
External IDs OMIM147620 MGI96559 HomoloGene502 GeneCards: IL6 Gene
RNA expression pattern
PBB GE IL6 205207 at.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3569 16193
Ensembl ENSG00000136244 ENSMUSG00000025746
UniProt P05231 Q0PMN1
RefSeq (mRNA) NM_000600.3 NM_031168.1
RefSeq (protein) NP_000591.1 NP_112445.1
Location (UCSC) Chr 7:
22.77 – 22.77 Mb
Chr 5:
30.34 – 30.35 Mb
PubMed search [1] [2]

Interleukin-6 (IL-6) is a protein that in humans is encoded by the IL6 gene.[1]

IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It 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. In terms of host response to a foreign pathogen during infection, IL-6 has been shown, in mice, to be required for resistance against the bacterium, Streptococcus pneumoniae.[2] IL-6 is also a "myokine," a cytokine produced from muscle, and is elevated in response to muscle contraction.[3] 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.[4] Additionally, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth muscle cells in the tunica media of many blood vessels also produce IL-6 as a pro-inflammatory cytokine. IL-6's role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-alpha and IL-1, and activation of IL-1ra and IL-10.

Contents

Function

IL-6 is one of the most important mediators of fever and of the acute phase response. It is capable of crossing the blood brain barrier[5] 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 which 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 highly 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. In a 2009 study, intranasally administered IL-6 was shown to improve sleep-associated consolidation of emotional memories.[6]

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.

Receptor

IL-6 signals through a cell-surface type I cytokine receptor complex consisting of the ligand-binding IL-6Rα chain (CD126), and the signal-transducing component gp130 (also called CD130). CD130 is the common signal transducer for several cytokines including leukemia inhibitory factor(LIF), ciliary neurotropic factor, oncostatin M, IL-11 and cardiotrophin-1, and is almost ubiquitously expressed in most tissues. In contrast, the expression of CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes bring together the intracellular regions of gp130 to initiate a signal transduction cascade through certain transcription factors, Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs).[7]

IL-6 is probably the best studied of the cytokines that use gp130, also known as IL-6 signal transducer (IL6ST), in their signalling complexes. Other cytokines that signal through receptors containing gp130 are Interleukin 11 (IL-11), Interleukin 27 (IL-27), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), leukemia inhibitory factor (LIF), oncostatin M (OSM), Kaposi's sarcoma-associated herpesvirus interleukin 6 like protein (KSHV-IL6).[8] These cytokines are commonly referred to as the IL-6 like or gp130 utilising cytokines [9]

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 promote survival of neurons, hence may be important in nerve regeneration through remyelination.

Interactions

Interleukin 6 has been shown to interact with interleukin-6 receptor.[10][11][12] and glycoprotein 130.[13]

Role in disease

IL-6 is relevant to many disease processes such as diabetes,[14] atherosclerosis,[15] depression,[16] Alzheimer's Disease,[17] systemic lupus erythematosus,[18] prostate cancer,[19] and rheumatoid arthritis.[20]

Advanced/metastatic cancer patients have higher levels of IL-6 in their blood.[21] Hence there is an interest in developing anti-IL-6 agents as therapy against many of these diseases.[22][23] The first such is tocilizumab which has been approved for rheumatoid arthritis. Another, ALD518, is in clinical trials.

References

  1. ^ 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". Genomics 2 (3): 203–208. doi:10.1016/0888-7543(88)90003-1. PMID 3294161. 
  2. ^ 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 Dis 176 (2): 439–444. doi:10.1086/514062. PMID 9237710. 
  3. ^ Febbraio MA, Pedersen BK (2005). "Contraction-induced myokine production and release: is skeletal muscle an endocrine organ?". Exerc Sport Sci Rev 33 (3): 114–119. doi:10.1097/00003677-200507000-00003. PMID 16006818. 
  4. ^ Petersen AM, Pedersen BK (April 2005). "The anti-inflammatory effect of exercise". J. Appl. Physiol. 98 (4): 1154–1162. doi:10.1152/japplphysiol.00164.2004. PMID 15772055. 
  5. ^ 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. PMID 7845624. 
  6. ^ 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. PMID 19546306. 
  7. ^ Heinrich PC, Behrmann, I, Müller-Newen G, Schaper F, Graeve L (1998). "Interleukin-6 type cytokine signalling through the gp130(Jak/STAT pathway". Biochem. J. 334: 297–314. PMC 1219691. PMID 9716487. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1219691. 
  8. ^ Kishimoto T, Akira S, Narazaki M, Taga T (1995). "Interleukin-6 family of cytokines and gp130". Blood 86 (4): 1243–54. PMID 7632928. 
  9. ^ Heinrich PC, Behrmann I, Haan, S, Hermanns, HM, Müller-Newen G, Schaper, F (2003). "Principles of interleukin-6-type cytokine signalling and its regulation". Biochem. J. 374 (Pt 1): 1–20. doi:10.1042/BJ20030407. PMC 1223585. PMID 12773095. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1223585. 
  10. ^ 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. PMID 14557255. 
  11. ^ 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. PMID 12643274. 
  12. ^ 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): 573–581. doi:10.1016/0092-8674(89)90438-8. PMID 2788034. 
  13. ^ Kallen KJ, zum Büschenfelde KH, Rose-John S (March 1997). "The therapeutic potential of interleukin-6 hyperagonists and antagonists". Expert Opin Investig Drugs 6 (3): 237–266. doi:10.1517/13543784.6.3.237. PMID 15989626. 
  14. ^ Kristiansen OP, Mandrup-Poulsen T (December 2005). "Interleukin-6 and diabetes: the good, the bad, or the indifferent?". Diabetes 54 Suppl 2: S114–24. PMID 16306329. 
  15. ^ Dubiński A, Zdrojewicz Z (April 2007). "[The role of interleukin-6 in development and progression of atherosclerosis]" (in Polish). Pol. Merkur. Lekarski 22 (130): 291–4. PMID 17684929. 
  16. ^ 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 Psychiatry 67 (5): 446–457. doi:10.1016/j.biopsych.2009.09.033. PMID 20015486. 
  17. ^ 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): 930–941. doi:10.1016/j.biopsych.2010.06.012. PMID 20692646. 
  18. ^ Tackey E, Lipsky PE, Illei GG (2004). "Rationale for interleukin-6 blockade in systemic lupus erythematosus". Lupus 13 (5): 339–343. doi:10.1191/0961203304lu1023oa. PMC 2014821. PMID 15230289. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2014821. 
  19. ^ Smith PC, Hobisch A, Lin DL, Culig Z, Keller ET (March 2001). "Interleukin-6 and prostate cancer progression". Cytokine Growth Factor Rev. 12 (1): 33–40. doi:10.1016/S1359-6101(00)00021-6. PMID 11312117. 
  20. ^ Nishimoto N (May 2006). "Interleukin-6 in rheumatoid arthritis". Curr Opin Rheumatol 18 (3): 277–281. doi:10.1097/01.bor.0000218949.19860.d1. PMID 16582692. 
  21. ^ "Cancer Patients Typically Have Increased Interleukin-6 Levels". American Society of Clinical Oncology 2006 Annual Meeting, Abstracts 8632 and 8633. Medscape.com. 2006-06-26. http://www.medscape.com/viewarticle/537309. 
  22. ^ Barton BE (August 2005). "Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes". Expert Opin. Ther. Targets 9 (4): 737–752. doi:10.1517/14728222.9.4.737. PMID 16083340. 
  23. ^ Smolen JS, Maini RN (2006). "Interleukin-6: a new therapeutic target". Arthritis Res. Ther. 8 Suppl 2: S5. doi:10.1186/ar1969. PMID 16899109. 

Further reading

  • 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): 121–134. doi:10.1016/0306-4530(94)90002-7. PMID 8190832. 
  • 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. PMID 12201209. 
  • Ishihara K, Hirano T (2003). "IL-6 in autoimmune disease and chronic inflammatory proliferative disease". Cytokine Growth Factor Rev. 13 (4–5): 357–368. doi:10.1016/S1359-6101(02)00027-8. PMID 12220549. 
  • Culig Z, Bartsch G, Hobisch A (2003). "Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth". Mol. Cell. Endocrinol. 197 (1–2): 231–238. doi:10.1016/S0303-7207(02)00263-0. PMID 12431817. 
  • Rattazzi M, Puato M, Faggin E et al. (2004). "C-reactive protein and interleukin-6 in vascular disease: culprits or passive bystanders?". J. Hypertens. 21 (10): 1787–803. PMID 14508181. 
  • 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. PMID 15609131. 
  • 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. PMID 15780075. 
  • Vgontzas AN, Bixler EO, Lin HM et al. (2005). "IL-6 and its circadian secretion in humans". Neuroimmunomodulation 12 (3): 131–140. doi:10.1159/000084844. PMID 15905620. 
  • Jones SA (2005). "Directing transition from innate to acquired immunity: defining a role for IL-6". J. Immunol. 175 (6): 3463–8. PMID 16148087. 
  • Copeland KF (2006). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini reviews in medicinal chemistry 5 (12): 1093–1101. doi:10.2174/138955705774933383. PMID 16375755. 
  • Mastorakos G, Ilias I (2007). "Interleukin-6: a cytokine and/or a major modulator of the response to somatic stress". Ann. N. Y. Acad. Sci. 1088: 373–381. doi:10.1196/annals.1366.021. PMID 17192581. 

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