Interleukin-17A

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene (O40633).^[5][6]

IL17A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2VXS, 4HR9, 4HSA, 4QHU, 5HHV, 5HHX
Identifiers
Aliases	IL17A, CTLA8, IL-17, IL-17A, IL17, CTLA-8, interleukin 17A, ILA17, Interleukin 17A
External IDs	OMIM: 603149 MGI: 107364 HomoloGene: 1651 GeneCards: IL17A
Gene location (Human) Chr. Chromosome 6 (human)^[1] Band 6p12.2 Start 52,186,375 bp^[1] End 52,190,638 bp^[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)^[2] Band 1|1 A4 Start 20,801,129 bp^[2] End 20,804,720 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in appendix pylorus palpebral conjunctiva gallbladder thymus human penis duodenum urinary bladder smooth muscle tissue rectum Top expressed in digastric muscle right ventricle submandibular gland carotid body ileum jejunum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine activity protein binding Cellular component external side of plasma membrane extracellular region extracellular space Biological process positive regulation of cytokine production involved in inflammatory response cell-cell signaling positive regulation of osteoclast differentiation cell death defense response to fungus cellular response to interleukin-1 immune response fibroblast activation positive regulation of interleukin-23 production positive regulation of transcription by RNA polymerase II apoptotic process inflammatory response regulation of signaling receptor activity cytokine-mediated signaling pathway interleukin-17-mediated signaling pathway granulocyte migration Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3605 16171 Ensembl ENSG00000112115 ENSMUSG00000025929 UniProt Q16552 Q62386 RefSeq (mRNA) NM_002190 NM_010552 RefSeq (protein) NP_002181 NP_034682 Location (UCSC) Chr 6: 52.19 – 52.19 Mb Chr 1: 20.8 – 20.8 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

The protein encoded by this gene is a proinflammatory cytokine produced by activated T cells. This cytokine regulates the activities of NF-kappaB and mitogen-activated protein kinases. This cytokine can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO).

Discovery

IL-17A, often referred to as IL-17, was originally discovered at transcriptional level by Rouvier et al. in 1993 from a rodent T-cell hybridoma, derived from the fusion of a mouse cytotoxic T cell clone and a rat T cell lymphoma.^[5] Human and mouse IL-17A were cloned a few years later by Yao^[7] and Kennedy.^[8] Lymphocytes including CD4+, CD8+, gamma-delta T (γδ-T), invariant NKT and innate lymphoid cells (ILCs) are primary sources of IL-17A.^[9] Non-T cells, such as neutrophils, have also been reported to produce IL-17A under certain circumstances.^[10] IL-17A producing T helper cells (Th17 cells) are a distinct lineage from the Th1 and Th2 CD4+ lineages and the differentiation of Th17 cells requires STAT3^[11] and RORC.^[12] IL-17A receptor A (IL-17RA) was first isolated and cloned from mouse EL4 thymoma cells and the bioactivity of IL-17A was confirmed by stimulating the transcriptional factor NF-kappa B activity and interleukin-6 (IL-6) secretion in fibroblasts.^[13] IL-17RA pairs with IL-17RC to allow binding and signaling of IL-17A and IL-17F.^[14]

Clinical significance

High levels of this cytokine are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis.^[6]

Autoimmune diseases

Multiple sclerosis (MS) is a neurological disease caused by immune cells, which attack and destroy the myelin sheath that insulates neurons in the brain and spinal cord. This disease and its animal model experimental autoimmune encephalomyelitis (EAE) have historically been associated with the discovery of Th17 cells.^[15][16] More current experiments on this animal model have also revealed that a key function of IL-17A in central nervous system (CNS) autoimmunity was to recruit IL-1β-secreting myeloid cells. These cells play a vital role in priming pathogenic Th17 cells, thus promoting the development of autoimmune disease.^[17] However, elevated expression of IL-17A in multiple sclerosis (MS) lesions as well as peripheral blood has been documented before the identification of Th17 cells.^[18][19] Human TH17 cells have been shown to efficiently transmigrate across the blood-brain barrier in multiple sclerosis lesions, promoting central nervous system inflammation.^[20]

Psoriasis is an auto-inflammatory skin disease characterized by circumscribed, crimson red, silver-scaled, plaque-like inflammatory lesions. Initially, psoriasis was considered to be a Th1-mediated disease since elevated levels of IFN-γ, TNF-α, and IL-12 was found in the serum and lesions of psoriasis patients.^[21] However, the finding of IL-17-producing cells as well as IL17A transcripts in the lesions of psoriatic patients suggested that Th17 cells may synergize with Th1 cells in driving the pathology in psoriasis.^[22][23] The levels of IL-17A in the synovium correlate with tissue damage, whereas levels of IFN-γ correlate with protection.^[24] Direct clinical significance of IL-17A in RA comes from recent clinical trials which found that two anti-IL-17A antibodies, namely secukinumab and ixekizumab significantly benefit these patients.^[25][26]

Th17 cells is also strongly associated rheumatoid arthritis (RA), a chronic disorder with symptoms include chronic joint inflammation, autoantibody production, which lead to the destruction of cartilage and bone.^[27]

Th17 cells and IL-17 have also been linked to Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel diseases (IBD). Th17 cells infiltrate massively to the inflamed tissue of IBD patients and both in vitro and in vivo studies have shown that Th17-related cytokines may initiate and amplify multiple pro-inflammatory pathways.^[28] Elevated IL-17A levels in IBD have been reported by several groups.^[29][30] Nonetheless, Th17 signature cytokines, such as IL-17A and IL-22, may target gut epithelial cells and promote the activation of regulatory pathways and confer protection in the gastrointestinal tract.^[31][32] To this end, recent clinical trials targeting IL-17A in IBD were negative and actually showed increased adverse events in the treatment arm.^[33] This data raised the question regarding the role of IL-17A in IBD pathogenesis and suggested that the elevated IL-17A might be beneficial for IBD patients.

Systemic lupus erythematosus, commonly referred as SLE or lupus, is a complex immune disorder affects the skin, joints, kidneys, and brain. Although the exact cause of lupus is not fully known, it has been reported that IL-17 and Th17 cells are involved in disease pathogenesis.^[34] It has been reported that serum IL-17 levels are also elevated in SLE patients compared to controls^[35][36] and the Th17 pathway has been shown to drive autoimmune responses in pre-clinical mouse models of lupus.^[37][38] More importantly, IL-17- and IL-17-producing cells have also been detected in kidney tissue and skin biopsies from SLE patients.^[39][40][41]

Lung diseases

Elevated levels of IL-17A have been found in the sputum and in bronchoalveolar lavage fluid of patients with asthma^[42] and a positive correlation between IL-17A production and asthma severity has been established.^[43] In murine models, treatment with dexamethasone inhibits the release of Th2-related cytokines but does not affect IL-17A production.^[44] Furthermore, Th17 cell-mediated airway inflammation and airway hyperresponsiveness are steroid resistant, indicating a potential role for Th17 cells in steroid-resistant asthma.^[44] However, a recent trial using anti-IL-17RA did not show efficacy in subjects with asthma.^[45]

Recent studies have suggested the involvement of immunological mechanisms in COPD.^[46] An increase in Th17 cells was observed in patients with COPD compared with current smokers without COPD and healthy subjects, and inverse correlations were found between Th17 cells with lung function.^[47] Gene expression profiling of bronchial brushings obtained from COPD patients also linked lung function to several Th17 signature genes such as SAA1, SAA2, SLC26A4 and LCN2.^[48] Animal studies have shown that cigarette smoke promotes pathogenic Th17 differentiation and induces emphysema,^[49] while blocking IL-17A using neutralizing antibody significantly decreased neutrophil recruitment and the pathological score of airway inflammation in tobacco-smoke-exposed mice.^[49][50]

Host defense

In host defense, IL-17A has been shown to be mostly beneficial against infection caused by extracellular bacteria and fungi.^[51] The primary function of Th17 cells appears to be control of the gut microbiota^[52][53] as well as the clearance of extracellular bacteria and fungi. IL-17A and IL-17 receptor signaling has been shown to be play a protective role in host defenses against many bacterial and fungal pathogens including Klebsiella pneumoniae, Mycoplasma pneumoniae, Candida albicans, Coccidioides posadasii, Histoplasma capsulatum, and Blastomyces dermatitidis.^[54] However, IL-17A seems to be detrimental in viral infection such as influenza through promoting neutrophilic inflammation.^[55]

The requirements of IL-17A and IL-17 receptor signaling in host defense were well documented and appreciated before the identification of Th17 cells as an independent T helper cell lineage. In experimental pneumonia models, IL-17A or IL-17RA knock mice have increased susceptibility to various Gram-negative bacteria, such as Klebsiella pneumoniae^[56] and Mycoplasma pneumoniae.^[57] In contrast, data suggest that IL-23 and IL-17A are not required for protection against primary infection by the intracellular bacteria Mycobacterium tuberculosis. Both the IL-17RA knock out mice and the IL-23p19 knock out mice cleared primary infection with M. tuberculosis.^[58][59] However, IL-17A is required for protection against primary infection with a different intracellular bacteria, Francisella tularensis.^[60]

Mouse model studies using the IL-17RA knock out mice and the IL-17A knock out mice with the murine adapted influenza strain (PR8)^[55] as well as the 2009 pandemic H1N1 strain [93] both support that IL-17A plays a detrimental role in mediating the acute lung injury.^[61]

The role of adaptive immune responses mediated by antigen specific Th17 has been investigated more recently. Antigen specific Th17 cells were also shown to recognize conserved protein antigens among different K. pneumoniae strains and provide broad-spectrum serotype-independent protection.^[62] Antigen specific CD4 T cells also limit nasopharyngeal colonization of S. pneumoniae in mouse models.^[63] Furthermore, immunization with pneumococcal whole cell antigen and several derivatives provided IL-17-mediated, but not antibody dependent, protection against S. pneumoniae challenge.^[64][65] In fungal infection, it has been shown an IL-17 producing clone with a TCR specific for calnexin from Blastomyces dermatitidis confers protection with evolutionary related fungal species including Histoplasma spp.^[66]

Cancer

In tumorigenesis, IL-17A has been shown to recruit myeloid derived suppressor cells (MDSCs) to dampen anti-tumor immunity.^[67][68] IL-17A can also enhance tumor growth in vivo through the induction of IL-6, which in turn activates oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) and upregulates pro-survival and pro-angiogenic genes in tumors.^[69] The exact role of IL-17A in angiogenesis has yet to be determined and current data suggest that IL-17A can promote or suppress tumor development.^[70] IL-17A seemed to facilitate development of colorectal carcinoma by fostering angiogenesis via promote VEGF production from cancer cells^[71] and it has been shown that IL-17A also mediates tumor resistance to anti-VEGF therapy through the recruitment of MDSCs.^[72]

However IL-17A KO mice were more susceptible to developing metastatic lung melanoma,^[73] suggesting that IL-17A can possibly promote the production of the potent antitumor cytokine IFN-γ, produced by cytotoxic T cells. Indeed, data from ovarian cancer suggest that Th17 cells are positively correlated with NK cell–mediated immunity and anti-tumor CD8 responses.^[74]

Ocular diseases

The presence of IL-17 has been proven in a number of ocular diseases associated with neovascularization. Elevated concentration of IL-17 have been shown in vitreous fluid during proliferative diabetic retinopathy. Increased rates of Th17 cells and higher concentrations of IL-17 have been observed in patients with age-related macular degeneration.^[75]

As a drug target

The discovery of the key roles of IL-17A and IL-17A producing cells in inflammation, autoimmune diseases and host defense has led to the experimental targeting of the IL-17A pathway in animal models of diseases as well as in clinical trials in humans. Targeting IL-17A has been proven to be a good approach as anti-IL-17A is FDA approved for the treatment of psoriasis in 2015.^[76]

Secukinumab (anti-IL-17A) has been evaluated in psoriasis and the first report showing Secukinumab is effective when compared with placebo was published in 2010.^[77] In 2015, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved anti-IL-17 for the treatment of psoriasis.^[78]

Other than the monoclonal antibodies, highly specific and potent inhibitors targeting Th17 specific transcription factor RORγt have been identified and found to be highly effective.^[79]

Vitamin D, a potent immunomodulator, has also been shown to suppress Th17 cell differentiation and function by several research groups.^[80] The active form of vitamin D has been found to 'severely impair'^[81] production of the IL17 and IL-17F cytokines by Th17 cells.

See also

• Interleukin 17

Notes

References

1. GRCh38: Ensembl release 89: ENSG00000112115 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025929 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Rouvier E, Luciani MF, Mattéi MG, Denizot F, Golstein P (June 1993). "CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene". Journal of Immunology. 150 (12): 5445–5456. doi:10.4049/jimmunol.150.12.5445. PMID 8390535. S2CID 5802339.
6. "Entrez Gene: IL17A interleukin 17A".
7. Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ (December 1995). "Human IL-17: a novel cytokine derived from T cells". Journal of Immunology. 155 (12): 5483–5486. doi:10.4049/jimmunol.155.12.5483. PMID 7499828. S2CID 23843306.
8. Kennedy J, Rossi DL, Zurawski SM, Vega F, Kastelein RA, Wagner JL, et al. (August 1996). "Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR + CD4-CD8-T cells". Journal of Interferon & Cytokine Research. 16 (8): 611–617. doi:10.1089/jir.1996.16.611. PMID 8877732.
9. Cua DJ, Tato CM (July 2010). "Innate IL-17-producing cells: the sentinels of the immune system". Nature Reviews. Immunology. 10 (7): 479–489. doi:10.1038/nri2800. PMID 20559326. S2CID 33426512.
10. Taylor PR, Roy S, Leal SM, Sun Y, Howell SJ, Cobb BA, et al. (February 2014). "Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORγt and dectin-2". Nature Immunology. 15 (2): 143–151. doi:10.1038/ni.2797. PMC 3972892. PMID 24362892.
11. Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O'Malley JT, et al. (April 2007). "Stat3 and Stat4 direct development of IL-17-secreting Th cells". Journal of Immunology. 178 (8): 4901–4907. doi:10.4049/jimmunol.178.8.4901. PMID 17404271.
12. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. (September 2006). "The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells". Cell. 126 (6): 1121–1133. doi:10.1016/j.cell.2006.07.035. PMID 16990136.
13. Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, et al. (December 1995). "Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor". Immunity. 3 (6): 811–821. doi:10.1016/1074-7613(95)90070-5. PMID 8777726.
14. Kuestner RE, Taft DW, Haran A, Brandt CS, Brender T, Lum K, et al. (October 2007). "Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F". Journal of Immunology. 179 (8): 5462–5473. doi:10.4049/jimmunol.179.8.5462. PMC 2849293. PMID 17911633.
15. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (November 2005). "Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages". Nature Immunology. 6 (11): 1123–1132. doi:10.1038/ni1254. PMID 16200070. S2CID 11717696.
16. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. (November 2005). "A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17". Nature Immunology. 6 (11): 1133–1141. doi:10.1038/ni1261. PMC 1618871. PMID 16200068.
17. McGinley AM, Sutton CE, Edwards SC, Leane CM, DeCourcey J, Teijeiro A, et al. (February 2020). "Interleukin-17A Serves a Priming Role in Autoimmunity by Recruiting IL-1β-Producing Myeloid Cells that Promote Pathogenic T Cells". Immunity. 52 (2): 342–356.e6. doi:10.1016/j.immuni.2020.01.002. hdl:2262/97198. PMID 32023490. S2CID 211045771.
18. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, et al. (May 2002). "Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis". Nature Medicine. 8 (5): 500–508. doi:10.1038/nm0502-500. PMID 11984595. S2CID 12258846.
19. Matusevicius D, Kivisäkk P, He B, Kostulas N, Ozenci V, Fredrikson S, Link H (April 1999). "Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis". Multiple Sclerosis. 5 (2): 101–104. doi:10.1177/135245859900500206. PMID 10335518. S2CID 45449835.
20. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, et al. (October 2007). "Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation". Nature Medicine. 13 (10): 1173–1175. doi:10.1038/nm1651. PMC 5114125. PMID 17828272.
21. Di Cesare A, Di Meglio P, Nestle FO (June 2009). "The IL-23/Th17 axis in the immunopathogenesis of psoriasis". The Journal of Investigative Dermatology. 129 (6): 1339–1350. doi:10.1038/jid.2009.59. PMID 19322214.
22. Harper EG, Guo C, Rizzo H, Lillis JV, Kurtz SE, Skorcheva I, et al. (September 2009). "Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis". The Journal of Investigative Dermatology. 129 (9): 2175–2183. doi:10.1038/jid.2009.65. PMC 2892172. PMID 19295614.
23. Cai Y, Shen X, Ding C, Qi C, Li K, Li X, et al. (October 2011). "Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation". Immunity. 35 (4): 596–610. doi:10.1016/j.immuni.2011.08.001. PMC 3205267. PMID 21982596.
24. Kirkham BW, Lassere MN, Edmonds JP, Juhasz KM, Bird PA, Lee CS, et al. (April 2006). "Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort)". Arthritis and Rheumatism. 54 (4): 1122–1131. doi:10.1002/art.21749. PMID 16572447.
25. Genovese MC, Van den Bosch F, Roberson SA, Bojin S, Biagini IM, Ryan P, Sloan-Lancaster J (April 2010). "LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study". Arthritis and Rheumatism. 62 (4): 929–939. doi:10.1002/art.27334. PMID 20131262.
26. Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Aelion JA, et al. (March 2014). "One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study". The Journal of Rheumatology. 41 (3): 414–421. doi:10.3899/jrheum.130637. PMID 24429175. S2CID 28119068.
27. McInnes IB, Schett G (December 2011). "The pathogenesis of rheumatoid arthritis". The New England Journal of Medicine. 365 (23): 2205–2219. doi:10.1056/NEJMra1004965. PMID 22150039. S2CID 17460029.
28. Monteleone I, Sarra M, Pallone F, Monteleone G (June 2012). "Th17-related cytokines in inflammatory bowel diseases: friends or foes?". Current Molecular Medicine. 12 (5): 592–597. doi:10.2174/156652412800620066. PMID 22515978.
29. Rovedatti L, Kudo T, Biancheri P, Sarra M, Knowles CH, Rampton DS, et al. (December 2009). "Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease". Gut. 58 (12): 1629–1636. doi:10.1136/gut.2009.182170. PMID 19740775. S2CID 25660771.
30. Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al. (January 2003). "Increased expression of interleukin 17 in inflammatory bowel disease". Gut. 52 (1): 65–70. doi:10.1136/gut.52.1.65. PMC 1773503. PMID 12477762.
31. Sarra M, Pallone F, Macdonald TT, Monteleone G (October 2010). "IL-23/IL-17 axis in IBD". Inflammatory Bowel Diseases. 16 (10): 1808–1813. doi:10.1002/ibd.21248. PMID 20222127. S2CID 10667403.
32. Li LJ, Gong C, Zhao MH, Feng BS (December 2014). "Role of interleukin-22 in inflammatory bowel disease". World Journal of Gastroenterology. 20 (48): 18177–18188. doi:10.3748/wjg.v20.i48.18177. PMC 4277955. PMID 25561785.
33. Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, et al. (December 2012). "Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial". Gut. 61 (12): 1693–1700. doi:10.1136/gutjnl-2011-301668. PMC 4902107. PMID 22595313.
34. Garrett-Sinha LA, John S, Gaffen SL (September 2008). "IL-17 and the Th17 lineage in systemic lupus erythematosus". Current Opinion in Rheumatology. 20 (5): 519–525. doi:10.1097/BOR.0b013e328304b6b5. PMID 18698171. S2CID 9653863.
35. Vincent FB, Northcott M, Hoi A, Mackay F, Morand EF (August 2013). "Clinical associations of serum interleukin-17 in systemic lupus erythematosus". Arthritis Research & Therapy. 15 (4): R97. doi:10.1186/ar4277. PMC 3979031. PMID 23968496.
36. Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW (June 2008). "Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity". Clinical Immunology. 127 (3): 385–393. doi:10.1016/j.clim.2008.01.019. PMID 18373953.
37. Jacob N, Yang H, Pricop L, Liu Y, Gao X, Zheng SG, et al. (February 2009). "Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway". Journal of Immunology. 182 (4): 2532–2541. doi:10.4049/jimmunol.0802948. PMC 2790862. PMID 19201910.
38. Hsu HC, Yang P, Wang J, Wu Q, Myers R, Chen J, et al. (February 2008). "Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice". Nature Immunology. 9 (2): 166–175. doi:10.1038/ni1552. hdl:10161/10221. PMID 18157131. S2CID 4842562.
39. Oh SH, Roh HJ, Kwon JE, Lee SH, Kim JY, Choi HJ, Lim BJ (July 2011). "Expression of interleukin-17 is correlated with interferon-α expression in cutaneous lesions of lupus erythematosus". Clinical and Experimental Dermatology. 36 (5): 512–520. doi:10.1111/j.1365-2230.2010.03996.x. PMID 21631571. S2CID 36351707.
40. Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X, et al. (May 2009). "Th17 and natural Treg cell population dynamics in systemic lupus erythematosus". Arthritis and Rheumatism. 60 (5): 1472–1483. doi:10.1002/art.24499. PMID 19404966.
41. Crispín JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, et al. (December 2008). "Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys". Journal of Immunology. 181 (12): 8761–8766. doi:10.4049/jimmunol.181.12.8761. PMC 2596652. PMID 19050297.
42. Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Pagé N, et al. (September 2001). "IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines". The Journal of Allergy and Clinical Immunology. 108 (3): 430–438. doi:10.1067/mai.2001.117929. PMID 11544464.
43. Chesné J, Braza F, Mahay G, Brouard S, Aronica M, Magnan A (November 2014). "IL-17 in severe asthma. Where do we stand?". American Journal of Respiratory and Critical Care Medicine. 190 (10): 1094–1101. doi:10.1164/rccm.201405-0859PP. PMID 25162311.
44. McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, et al. (September 2008). "TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice". Journal of Immunology. 181 (6): 4089–4097. doi:10.4049/jimmunol.181.6.4089. PMC 3638757. PMID 18768865.
45. Busse WW, Holgate S, Kerwin E, Chon Y, Feng J, Lin J, Lin SL (December 2013). "Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma". American Journal of Respiratory and Critical Care Medicine. 188 (11): 1294–1302. doi:10.1164/rccm.201212-2318OC. PMID 24200404.
46. Alcorn JF, Crowe CR, Kolls JK (2010). "TH17 cells in asthma and COPD". Annual Review of Physiology. 72: 495–516. doi:10.1146/annurev-physiol-021909-135926. PMID 20148686.
47. Vargas-Rojas MI, Ramírez-Venegas A, Limón-Camacho L, Ochoa L, Hernández-Zenteno R, Sansores RH (November 2011). "Increase of Th17 cells in peripheral blood of patients with chronic obstructive pulmonary disease". Respiratory Medicine. 105 (11): 1648–1654. doi:10.1016/j.rmed.2011.05.017. PMID 21763119.
48. Steiling K, van den Berge M, Hijazi K, Florido R, Campbell J, Liu G, et al. (May 2013). "A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment". American Journal of Respiratory and Critical Care Medicine. 187 (9): 933–942. doi:10.1164/rccm.201208-1449OC. PMC 3707363. PMID 23471465.
49. Chen K, Pociask DA, McAleer JP, Chan YR, Alcorn JF, Kreindler JL, et al. (2011). "IL-17RA is required for CCL2 expression, macrophage recruitment, and emphysema in response to cigarette smoke". PLOS ONE. 6 (5): e20333. Bibcode:2011PLoSO...620333C. doi:10.1371/journal.pone.0020333. PMC 3103542. PMID 21647421.
50. Shen N, Wang J, Zhao M, Pei F, He B (March 2011). "Anti-interleukin-17 antibodies attenuate airway inflammation in tobacco-smoke-exposed mice". Inhalation Toxicology. 23 (4): 212–218. Bibcode:2011InhTx..23..212S. doi:10.3109/08958378.2011.559603. PMID 21456954. S2CID 30211058.
51. Kolls JK, Khader SA (December 2010). "The role of Th17 cytokines in primary mucosal immunity". Cytokine & Growth Factor Reviews. 21 (6): 443–448. doi:10.1016/j.cytogfr.2010.11.002. PMC 3004678. PMID 21095154.
52. Kumar P, Monin L, Castillo P, Elsegeiny W, Horne W, Eddens T, et al. (March 2016). "Intestinal Interleukin-17 Receptor Signaling Mediates Reciprocal Control of the Gut Microbiota and Autoimmune Inflammation". Immunity. 44 (3): 659–671. doi:10.1016/j.immuni.2016.02.007. PMC 4794750. PMID 26982366.
53. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. (October 2009). "Induction of intestinal Th17 cells by segmented filamentous bacteria". Cell. 139 (3): 485–498. doi:10.1016/j.cell.2009.09.033. PMC 2796826. PMID 19836068.
54. Chen K, Kolls JK (2013). "T cell-mediated host immune defenses in the lung". Annual Review of Immunology. 31: 605–633. doi:10.1146/annurev-immunol-032712-100019. PMC 3912562. PMID 23516986.
55. Crowe CR, Chen K, Pociask DA, Alcorn JF, Krivich C, Enelow RI, et al. (October 2009). "Critical role of IL-17RA in immunopathology of influenza infection". Journal of Immunology. 183 (8): 5301–5310. doi:10.4049/jimmunol.0900995. PMC 3638739. PMID 19783685.
56. Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, et al. (August 2001). "Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense". The Journal of Experimental Medicine. 194 (4): 519–527. doi:10.1084/jem.194.4.519. PMC 2193502. PMID 11514607.
57. Wu Q, Martin RJ, Rino JG, Breed R, Torres RM, Chu HW (January 2007). "IL-23-dependent IL-17 production is essential in neutrophil recruitment and activity in mouse lung defense against respiratory Mycoplasma pneumoniae infection". Microbes and Infection. 9 (1): 78–86. doi:10.1016/j.micinf.2006.10.012. PMC 1832075. PMID 17198762.
58. Khader SA, Pearl JE, Sakamoto K, Gilmartin L, Bell GK, Jelley-Gibbs DM, et al. (July 2005). "IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-gamma responses if IL-12p70 is available". Journal of Immunology. 175 (2): 788–795. doi:10.4049/jimmunol.175.2.788. PMID 16002675.
59. Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ, et al. (September 2005). "Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae". The Journal of Experimental Medicine. 202 (6): 761–769. doi:10.1084/jem.20050193. PMC 2212952. PMID 16157683.
60. Lin Y, Ritchea S, Logar A, Slight S, Messmer M, Rangel-Moreno J, et al. (November 2009). "Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis". Immunity. 31 (5): 799–810. doi:10.1016/j.immuni.2009.08.025. PMC 2789998. PMID 19853481.
61. Li C, Yang P, Sun Y, Li T, Wang C, Wang Z, et al. (March 2012). "IL-17 response mediates acute lung injury induced by the 2009 pandemic influenza A (H1N1) virus". Cell Research. 22 (3): 528–538. doi:10.1038/cr.2011.165. PMC 3292301. PMID 22025253.
62. Chen K, McAleer JP, Lin Y, Paterson DL, Zheng M, Alcorn JF, et al. (December 2011). "Th17 cells mediate clade-specific, serotype-independent mucosal immunity". Immunity. 35 (6): 997–1009. doi:10.1016/j.immuni.2011.10.018. PMC 3406408. PMID 22195749.
63. Trzciński K, Thompson CM, Srivastava A, Basset A, Malley R, Lipsitch M (June 2008). "Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells". Infection and Immunity. 76 (6): 2678–2684. doi:10.1128/IAI.00141-08. PMC 2423086. PMID 18391006.
64. Malley R, Srivastava A, Lipsitch M, Thompson CM, Watkins C, Tzianabos A, Anderson PW (April 2006). "Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide". Infection and Immunity. 74 (4): 2187–2195. doi:10.1128/IAI.74.4.2187-2195.2006. PMC 1418935. PMID 16552049.
65. Lu YJ, Gross J, Bogaert D, Finn A, Bagrade L, Zhang Q, et al. (September 2008). "Interleukin-17A mediates acquired immunity to pneumococcal colonization". PLOS Pathogens. 4 (9): e1000159. doi:10.1371/journal.ppat.1000159. PMC 2528945. PMID 18802458.
66. Wüthrich M, Brandhorst TT, Sullivan TD, Filutowicz H, Sterkel A, Stewart D, et al. (April 2015). "Calnexin induces expansion of antigen-specific CD4(+) T cells that confer immunity to fungal ascomycetes via conserved epitopes". Cell Host & Microbe. 17 (4): 452–465. doi:10.1016/j.chom.2015.02.009. PMC 4484745. PMID 25800545.
67. He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, Xu H (March 2010). "IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells". Journal of Immunology. 184 (5): 2281–2288. doi:10.4049/jimmunol.0902574. PMC 3179912. PMID 20118280.
68. Chang SH, Mirabolfathinejad SG, Katta H, Cumpian AM, Gong L, Caetano MS, et al. (April 2014). "T helper 17 cells play a critical pathogenic role in lung cancer". Proceedings of the National Academy of Sciences of the United States of America. 111 (15): 5664–5669. Bibcode:2014PNAS..111.5664C. doi:10.1073/pnas.1319051111. PMC 3992670. PMID 24706787.
69. Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H (July 2009). "IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway". The Journal of Experimental Medicine. 206 (7): 1457–1464. doi:10.1084/jem.20090207. PMC 2715087. PMID 19564351.
70. Houghton AM (April 2013). "Mechanistic links between COPD and lung cancer". Nature Reviews. Cancer. 13 (4): 233–245. doi:10.1038/nrc3477. PMID 23467302. S2CID 5050984.
71. Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, et al. (April 2011). "IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma". Biochemical and Biophysical Research Communications. 407 (2): 348–354. doi:10.1016/j.bbrc.2011.03.021. PMID 21396350.
72. Maniati E, Hagemann T (September 2013). "IL-17 mediates resistance to anti-VEGF therapy". Nature Medicine. 19 (9): 1092–1094. doi:10.1038/nm.3333. PMID 24013745. S2CID 205391999.
73. Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, et al. (November 2009). "T helper 17 cells promote cytotoxic T cell activation in tumor immunity". Immunity. 31 (5): 787–798. doi:10.1016/j.immuni.2009.09.014. PMC 2787786. PMID 19879162.
74. Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, et al. (August 2009). "Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments". Blood. 114 (6): 1141–1149. doi:10.1182/blood-2009-03-208249. PMC 2723011. PMID 19470694.
75. Li Y, Zhou Y (February 2019). "Interleukin-17: The Role for Pathological Angiogenesis in Ocular Neovascular Diseases". The Tohoku Journal of Experimental Medicine. 247 (2): 87–98. doi:10.1620/tjem.247.87. PMID 30773517.
76. "FDA approves new psoriasis drug Cosentyx". U.S. Food and Drug Administration. 21 January 2015.
77. Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. (October 2010). "Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis". Science Translational Medicine. 2 (52): 52ra72. doi:10.1126/scitranslmed.3001107. PMID 20926833.
78. Beringer A, Noack M, Miossec P (March 2016). "IL-17 in Chronic Inflammation: From Discovery to Targeting". Trends in Molecular Medicine. 22 (3): 230–241. doi:10.1016/j.molmed.2016.01.001. PMID 26837266.
79. Huh JR, Littman DR (September 2012). "Small molecule inhibitors of RORγt: targeting Th17 cells and other applications". European Journal of Immunology. 42 (9): 2232–2237. doi:10.1002/eji.201242740. PMC 3609417. PMID 22949321.
80. Hayes CE, Hubler SL, Moore JR, Barta LE, Praska CE, Nashold FE (18 March 2015). "Vitamin D Actions on CD4(+) T Cells in Autoimmune Disease". Frontiers in Immunology. 6: 100. doi:10.3389/fimmu.2015.00100. PMC 4364365. PMID 25852682.
81. Chang SH, Chung Y, Dong C (December 2010). "Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression". The Journal of Biological Chemistry. 285 (50): 38751–38755. doi:10.1074/jbc.C110.185777. PMC 2998156. PMID 20974859.

Further reading

• Gaffen SL (2005). "Biology of recently discovered cytokines: interleukin-17--a unique inflammatory cytokine with roles in bone biology and arthritis". Arthritis Research & Therapy. 6 (6): 240–247. doi:10.1186/ar1444. PMC 1064872. PMID 15535837.
• Lubberts E, Koenders MI, van den Berg WB (2006). "The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models". Arthritis Research & Therapy. 7 (1): 29–37. doi:10.1186/ar1478. PMC 1064899. PMID 15642151.
• Fossiez F, Djossou O, Chomarat P, Flores-Romo L, Ait-Yahia S, Maat C, et al. (June 1996). "T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines". The Journal of Experimental Medicine. 183 (6): 2593–2603. doi:10.1084/jem.183.6.2593. PMC 2192621. PMID 8676080.
• Yao Z, Spriggs MK, Derry JM, Strockbine L, Park LS, VandenBos T, et al. (November 1997). "Molecular characterization of the human interleukin (IL)-17 receptor". Cytokine. 9 (11): 794–800. doi:10.1006/cyto.1997.0240. PMID 9367539.
• Murphy KP, Gagne P, Pazmany C, Moody MD (March 1998). "Expression of human interleukin-17 in Pichia pastoris: purification and characterization". Protein Expression and Purification. 12 (2): 208–214. doi:10.1006/prep.1997.0832. PMID 9518462.
• Teunissen MB, Koomen CW, de Waal Malefyt R, Wierenga EA, Bos JD (October 1998). "Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes". The Journal of Investigative Dermatology. 111 (4): 645–649. doi:10.1046/j.1523-1747.1998.00347.x. PMID 9764847.
• Shalom-Barak T, Quach J, Lotz M (October 1998). "Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB". The Journal of Biological Chemistry. 273 (42): 27467–27473. doi:10.1074/jbc.273.42.27467. PMID 9765276.
• Shin HC, Benbernou N, Fekkar H, Esnault S, Guenounou M (November 1998). "Regulation of IL-17, IFN-gamma and IL-10 in human CD8(+) T cells by cyclic AMP-dependent signal transduction pathway". Cytokine. 10 (11): 841–850. doi:10.1006/cyto.1998.0375. PMID 9878122.
• Laan M, Cui ZH, Hoshino H, Lötvall J, Sjöstrand M, Gruenert DC, et al. (February 1999). "Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways". Journal of Immunology. 162 (4): 2347–2352. doi:10.4049/jimmunol.162.4.2347. PMID 9973514. S2CID 12318929.
• Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. (May 1999). "IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis". The Journal of Clinical Investigation. 103 (9): 1345–1352. doi:10.1172/JCI5703. PMC 408356. PMID 10225978.
• Shin HC, Benbernou N, Esnault S, Guenounou M (April 1999). "Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway". Cytokine. 11 (4): 257–266. doi:10.1006/cyto.1998.0433. PMID 10328864.
• Andoh A, Takaya H, Makino J, Sato H, Bamba S, Araki Y, et al. (July 2001). "Cooperation of interleukin-17 and interferon-gamma on chemokine secretion in human fetal intestinal epithelial cells". Clinical and Experimental Immunology. 125 (1): 56–63. doi:10.1046/j.1365-2249.2001.01588.x. PMC 1906093. PMID 11472426.
• Laan M, Palmberg L, Larsson K, Lindén A (March 2002). "Free, soluble interleukin-17 protein during severe inflammation in human airways". The European Respiratory Journal. 19 (3): 534–537. doi:10.1183/09031936.02.00280902. PMID 11936535.
• Andoh A, Fujino S, Bamba S, Araki Y, Okuno T, Bamba T, Fujiyama Y (August 2002). "IL-17 selectively down-regulates TNF-alpha-induced RANTES gene expression in human colonic subepithelial myofibroblasts". Journal of Immunology. 169 (4): 1683–1687. doi:10.4049/jimmunol.169.4.1683. PMID 12165487.
• Andoh A, Shimada M, Bamba S, Okuno T, Araki Y, Fujiyama Y, Bamba T (August 2002). "Extracellular signal-regulated kinases 1 and 2 participate in interleukin-17 plus tumor necrosis factor-alpha-induced stabilization of interleukin-6 mRNA in human pancreatic myofibroblasts". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1591 (1–3): 69–74. doi:10.1016/S0167-4889(02)00250-1. PMID 12183057.
• Hsieh HG, Loong CC, Lin CY (August 2002). "Interleukin-17 induces src/MAPK cascades activation in human renal epithelial cells". Cytokine. 19 (4): 159–174. doi:10.1006/cyto.2002.1952. PMID 12297109.
• Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL (January 2003). "Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17". The Journal of Biological Chemistry. 278 (3): 1910–1914. doi:10.1074/jbc.M207577200. PMID 12417590.

External links

• Overview of all the structural information available in the PDB for UniProt: Q16552 (Interleukin-17A) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.