Interleukin 6

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Interleukin 6 (interferon, beta 2)

PDB rendering based on 1ALU.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols IL6; BSF2; HGF; HSF; IFNB2; IL-6
External IDs OMIM: 147620 MGI: 96559 HomoloGene: 502 ChEMBL: 1795129 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 P08505
RefSeq (mRNA) NM_000600 NM_031168
RefSeq (protein) NP_000591 NP_112445
Location (UCSC) Chr 7:
22.77 – 22.77 Mb		 Chr 5:
30.01 – 30.02 Mb
PubMed search [1] [2]
This box:

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. In humans, it is encoded by the IL6 gene.[1]

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.[2]

IL-6 is also considered 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 [edit]

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.[6] In a 2009 study, intranasally administered IL-6 was shown to improve sleep-associated consolidation of emotional memories.[7]

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 [edit]

Main article: Interleukin-6 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).[8]

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).[9] These cytokines are commonly referred to as the IL-6 like or gp130 utilising cytokines [10]

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 [edit]

Interleukin 6 has been shown to interact with interleukin-6 receptor.[11][12][13] and glycoprotein 130.[14]

Role in disease [edit]

IL-6 is relevant to many diseases such as diabetes,[15] atherosclerosis,[16] depression,[17] Alzheimer's Disease,[18] systemic lupus erythematosus,[19] multiple myeloma,[20] prostate cancer,[21]behcet's disease,[22] and rheumatoid arthritis.[23]

Advanced/metastatic cancer patients have higher levels of IL-6 in their blood.[24] Hence there is an interest in developing anti-IL-6 agents as therapy against many of these diseases.[25][26] The first such is tocilizumab which has been approved for rheumatoid arthritis. Another, ALD518, is in clinical trials.

Epigenetic modifications and disease [edit]

IL-6 has been shown to lead to several neurological diseases through its impact on epigenetic modification within the brain [27][28][29][30] 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).[31] This phosphorylation causes movement of DNMT1 to the nucleus, where it can be transcribed.[31] DNMT1 recruits other DNMTs, including DNMT3A and DNMT3B, which, as a complex, recruit HDAC1.[30] 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.[30] Increased IL-6, therefore, can hypermethylate DNA sequences and subsequently decrease gene expression through its effects on DNMT1 expression.[29]

Schizophrenia [edit]

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.[30] This hypermethylation may potentially lead to the decreased GAD67 levels seen in schizophrenic brains.[32] GAD67 may be involved in the pathology of schizophrenia through its effect on GABA levels and on neural oscillations.[33] 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.[33] These neural oscillations are impaired in schizophrenics, and these alterations may be responsible for both positive and negative symptoms of schizophrenia.[34]

Depression [edit]

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.[35] Altered BDNF function has been implicated in depression,[36] which is likely due to epigenetic modification following IL-6 upregulation.[35] BDNF is a neutrophic factor that is implicated in spine formation, density and morphology on neurons.[37] Downregulation of BDNF, therefore, may cause decreased connectivity in the brain. Depression is marked by altered connectivity, particularly between the anterior cingulate cortex and several other limbic areas, such as the hippocampus.[38] The anterior cingulate cortex is responsible for detecting incongruences between expectation and perceived experience.[39] Altered connectivity of the anterior cingulate cortex in depression, therefore, may cause altered emotions following certain experiences, leading to depressive reactions.[39] This altered connectivity is mediated by IL-6 and its effect on epigenetic regulation of BDNF.[35]

References [edit]

  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. ^ 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. 
  7. ^ 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. 
  8. ^ 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 (Pt 2): 297–314. PMC 1219691. PMID 9716487. 
  9. ^ Kishimoto T, Akira S, Narazaki M, Taga T (1995). "Interleukin-6 family of cytokines and gp130". Blood 86 (4): 1243–54. PMID 7632928. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ Kristiansen OP, Mandrup-Poulsen T (December 2005). "Interleukin-6 and diabetes: the good, the bad, or the indifferent?". Diabetes. 54 Suppl 2: S114–24. doi:10.2337/diabetes.54.suppl_2.S114. PMID 16306329. 
  16. ^ 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. PMID 17684929. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ Gadó K, Domján G, Hegyesi H, Falus A (2000). "Role of INTERLEUKIN-6 in the pathogenesis of multiple myeloma". Cell Biol. Int. 24 (4): 195–209. doi:10.1006/cbir.2000.0497. PMID 10816321. 
  21. ^ 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. 
  22. ^ 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.51.85834. PMID 23257520. 
  23. ^ 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. 
  24. ^ "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. 
  25. ^ 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. 
  26. ^ Smolen JS, Maini RN (2006). "Interleukin-6: a new therapeutic target". Arthritis Res. Ther. 8 Suppl 2 (Suppl 2): S5. doi:10.1186/ar1969. PMC 3226077. PMID 16899109. 
  27. ^ Smith, S. E. P.; Li, J.; Garbett, K.; Mirnics, K.; Patterson, P. H. (2007). "Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6". Journal of Neuroscience 27 (40): 10695–10702. doi:10.1523/JNEUROSCI.2178-07.2007. PMC 2387067. PMID 17913903.  edit
  28. ^ Kaiser, L.; Fritz, R. S.; Straus, S. E.; Gubareva, L.; Hayden, F. G. (2001). "Symptom pathogenesis during acute influenza: Interleukin-6 and Other cytokine responses". Journal of Medical Virology 64 (3): 262–268. doi:10.1002/jmv.1045. PMID 11424113.  edit
  29. ^ a b Foran, E.; Garrity-Park, M. M.; Mureau, C.; Newell, J.; Smyrk, T. C.; Limburg, P. J.; Egan, L. J. (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): 471–481. doi:10.1158/1541-7786.MCR-09-0496. PMID 20354000.  edit
  30. ^ a b c d Kundakovic, M.; Chen, Y.; Guidotti, A.; Grayson, D. R. (2008). "The Reelin and GAD67 Promoters Are Activated by Epigenetic Drugs That Facilitate the Disruption of Local Repressor Complexes". Molecular Pharmacology 75 (2): 342–354. doi:10.1124/mol.108.051763. PMC 2684898. PMID 19029285.  edit
  31. ^ a b Hodge, D. R.; Cho, E.; Copeland, T. D.; Guszczynski, T.; Yang, E.; Seth, A. K.; Farrar, W. L. (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): 387–398. PMID 18204201.  edit
  32. ^ Guidotti, A.; Auta, J.; Davis, J. M.; Di-Giorgi-Gerevini, V.; Dwivedi, Y.; Grayson, D. R.; Impagnatiello, F.; Pandey, G. et al. (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): 1061–1069. doi:10.1001/archpsyc.57.11.1061. PMID 11074872.   edit
  33. ^ a b Gandal, M. J.; Sisti, J.; Klook, K.; Ortinski, P. I.; Leitman, V.; Liang, Y.; Thieu, T.; Anderson, R. et al. (2012). "GABAB-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction". Translational Psychiatry 2 (7): e142–. doi:10.1038/tp.2012.69. PMC 3410621. PMID 22806213.   edit
  34. ^ Uhlhaas, P. J.; Singer, W. (2010). "Abnormal neural oscillations and synchrony in schizophrenia". Nature Reviews Neuroscience 11 (2): 100–113. doi:10.1038/nrn2774. PMID 20087360.  edit
  35. ^ a b c Sharma, R. P.; Tun, N.; Grayson, D. R. (2008). "Depolarization induces downregulation of DNMT1 and DNMT3a in primary cortical cultures". Epigenetics : official journal of the DNA Methylation Society 3 (2): 74–80. doi:10.4161/epi.3.2.6103. PMID 18536530.  edit
  36. ^ Hwang, J. P.; Tsai, S. J.; Hong, C. J.; Yang, C. H.; Lirng, J. F.; Yang, Y. M. (2006). "The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression". Neurobiology of Aging 27 (12): 1834–1837. doi:10.1016/j.neurobiolaging.2005.10.013. PMID 16343697.  edit
  37. ^ Ethell, I. M.; Pasquale, E. B. (2005). "Molecular mechanisms of dendritic spine development and remodeling". Progress in Neurobiology 75 (3): 161–205. doi:10.1016/j.pneurobio.2005.02.003. PMID 15882774.  edit
  38. ^ Greicius, M. D.; Flores, B. H.; Menon, V.; Glover, G. H.; Solvason, H. B.; Kenna, H.; Reiss, A. L.; Schatzberg, A. F. (2007). "Resting-State Functional Connectivity in Major Depression: Abnormally Increased Contributions from Subgenual Cingulate Cortex and Thalamus". Biological Psychiatry 62 (5): 429–437. doi:10.1016/j.biopsych.2006.09.020. PMC 2001244. PMID 17210143.  edit
  39. ^ a b Somerville, L. H.; Heatherton, T. F.; Kelley, W. M. (2006). "Anterior cingulate cortex responds differentially to expectancy violation and social rejection". Nature Neuroscience 9 (8): 1007–1008. doi:10.1038/nn1728. PMID 16819523.  edit

Further reading [edit]

  • 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. doi:10.1097/00004872-200310000-00002. 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. 

External links [edit]
By family
Chemokine
CCL
CXCL
CX3CL
XCL
TNF
Interleukin
Type I
(grouped by
receptor
subunit)
γ-chain
β-chain
IL6 like/gp130
IL-12 family/IL12RB1
Other
Type II
IL-10 family
Interferon
I
II
Ig superfamily
IL-17 family
Other
By function/
cell
Retrieved from "http://en.wikipedia.org/w/index.php?title=Interleukin_6&oldid=555331633"