LECTURE SERIES - INTERLEUKIN 17 (IL17) 

IL17ppt.PNG

Interleukin-17 | IL17

  • Interleukin-17A (IL-17A) is the prototypic member of the IL-17 family of cytokines. IL-17A plays a critical role in host defense and inflammation.

  • IL-17A expression is most often associated with the T helper 17 (TH17) subset of CD4+ T cells, but has also been observed in CD8+ T cells, neutrophils, and γδ T cells upon stimulation with IL-1 and IL-23. IL-17A is most similarly related to IL-17F with which it shares 50% sequence homology. Both IL-17A and IL-17F exist as either biologically active homodimers (IL-17AA and IL-17FF) or biologically active heterodimers (IL-17AF). All three protein complexes are currently believed to signal through the same receptor complex (IL-17R) composed of the subunits IL-17RA and IL-17RC (IL-17RL), though they appear to have different biological functions.

  • One of the principle IL-17 functions appears to be the regulation of local tissue inflammation via the coordinated expression of various cytokines and chemokines that include IL-1, IL-6, IL-8, GM-CSF, G-CSF, TNF, CXCL1, MCP-1, MIP-2, MCP-3, and MIP-3α. Upon ligand/receptor interaction, IL-17A induces these inflammatory cytokine production in epithelial cells, endothelial cells, and fibroblasts through the NFκB and MAPK family pathways that results in the activation of many of the AP-1 proteins. IL-17 has become an important target for drug discovery for the treatment of various forms of autoimmunity and inflammatory diseases such as asthma, rheumatoid arthritis, multiple sclerosis, psoriasis, transplant rejection, and inflammatory bowel disease (IBD).

  • IL-17 is a proinflammatory cytokine produced by activated T cells. IL-17 regulates the activities of NF-kappa B and mitogen-activated protein kinases. IL17 can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO).

  • High levels of IL-17 are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis. The original described IL-17 protein, now known as IL-17A, was identified from a CD4+ T cells DNA library. IL-17 can be induced from primary peripheral blood CD4+ T cells upon stimulation. Supernatant from cells transfected with IL-17 induced IL-16 and IL-18 production and enhanced the surface expression of the intracellular adhesion molecule-1 (ICAM-1) in human fibroblasts.

  • Interleukin-17 facilitates the immune suppressor capacity of high-grade glioma-derived CD4 (+) CD25 (+) Foxp3 (+) T cells via releasing transforming growth factor beta.

  • IL-17A exerts various biological activities that could promote tissue destruction and degeneration during inflammation. In particular, it induces the production, often in a synergistic manner, of cytokines, including IL-1, IL-6, TNF-α, chemokines, inducible NO synthase, and matrix metalloproteinases (MMPs) by fibroblasts, macrophages, and endothelial cells21. Experimental models provide evidence for an early inflammatory response in tendinopathy2,22,23

  • Recently we have shown a distinct inflammatory infiltrate in early human tendinopathy24 and increased levels of proinflammatory cytokines including TNF-α, IL-6 in torn supraspinatus samples25. A recent transcriptomic analysis has highlighted increased expression of IL-17F in human tendinopathy biopsies26. Based on these observations and the plausible biological profile exhibited by IL-17A, we hypothesized that IL-17A may play a role in tendinopathy.

Leukoc Biol. 2016 Apr 21. pii: jlb.4A0715-331R. [Epub ahead of print]

Autophagy suppresses host adaptive immune responses toward Borrelia burgdorferi

Buffen K1, Oosting M1, Li Y2, Kanneganti TD3, Netea MG1, Joosten LA4.

Author information

  • 1Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands;

  • 2University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands; and.

  • 3Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

  • 4Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands; leo.joosten@radboudumc.nl.

Abstract

We have previously demonstrated that inhibition of autophagy increased the Borrelia burgdorferi induced innate cytokine production in vitro, but little is known regarding the effect of autophagy on in vivo models of Borrelia infection. Here, we showed that ATG7-deficient mice that were intra-articular injected with Borrelia spirochetes displayed increased joint swelling, cell influx, and enhanced interleukin-1β and interleukin-6 production by inflamed synovial tissue. Because both interleukin-1β and interleukin-6 are linked to the development of adaptive immune responses, we examine the function of autophagy on Borrelia induced adaptive immunity.

Human peripheral blood mononuclear cells treated with autophagy inhibitors showed an increase in interleukin-17, interleukin-22, and interferon-γ production in response to exposure to Borrelia burgdorferi. Increased IL-17 production was dependent on IL-1β release but, interestingly, not on interleukin-23 production. In addition, cytokine quantitative trait loci in ATG9B modulate the Borrelia induced interleukin-17 production.

  • Because high levels of IL-17 have been found in patients with confirmed, severe, chronic borreliosis, we propose that the modulation of autophagy may be a potential target for anti-inflammatory therapy in patients with persistent Lyme disease.

Curr Rheumatol Rep. 2016 Jun;18(6):33. doi: 10.1007/s11926-016-0585-9.

The Bench-to-Bedside Story of IL-17 and the Therapeutic Efficacy of its Targeting in Spondyloarthritis

Smith JA1.

Author information

  • 1Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, 600 Highland Ave, Madison, WI, 53792-4108, USA. Jsmith27@pediatrics.wisc.edu.

Abstract

TNF-blocking biologics have revolutionized the care of patients with spondyloarthritis, a group of clinically overlapping conditions that includes ankylosing spondylitis and psoriatic arthritis. However, incomplete response rates speak to the need for alternative therapeutic approaches.

Over the last decade, animal models, genetics, and translational studies have implicated the excessive production of a pro-inflammatory cytokine interleukin-17 (IL-17) along with another IL-17-promoting cytokine IL-23 in the pathogenesis of spondyloarthritis. Genome-wide studies identified disease associations with multiple genes regulating IL-23/IL-17 immune pathway activity. Direct examination of the patient blood and tissues revealed excessive IL-17 and IL-23 production by diverse cell types. Murine models both underscored the sufficiency of excess IL-23 in driving disease phenotype and predicted utility in IL-23/IL-17 pathway blockade. However, the clinical efficacy of agents such as secukinumab and ustekinumab, which block IL-17 and IL-23/IL-12 respectively, provided exciting proof of concept.

Cent Eur J Immunol. 2016;41(1):78-85. doi: 10.5114/ceji.2016.58819. Epub 2016 Mar 24.

Reduced levels of T-helper 17-associated cytokines in the serum of patients with breast cancer: indicators for following the course of disease

Baharlou R1, Atashzar MR1, Vasmehjani AA1, Rahimi E2, Khoshmirsafa M1, Seif F1, Mahdiyar M3.

Author information

  • 1Department of Immunology and Microbiology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.

  • 2Department of Social Medicine, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.

  • 3Department of Student Research Committee, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.

Abstract

Interleukin (IL)-17-producing CD4(+) T helper (Th17) cells that are known to produce IL-17 have recently been defined as a unique subset of proinflammatory helper cells. Interleukin 17 is an inflammatory cytokine with robust effects on many cells. It can play important roles in the pathogenesis of diverse groups of immune-mediated diseases. In this regard, the present case-control study aimed at determining serum levels of IL-17, IL-6, and transforming growth factor β (TGF-β) in Iranian breast cancer patients. Blood samples were collected from 55 patients with breast cancer and 34 healthy individuals with no history of malignancies or autoimmune disorders, based on simple sampling. The serum levels of IL-17, IL-6 and TGF-β were measured by enzyme-linked immunosorbent assay (ELISA). The serum level of IL-6 was significantly lower in patients with breast cancer compared with healthy individuals (p = 0.0003), and also the IL-17 was lower in the patient group than in controls (p = 0.01). Interestingly, the TGF-β serum level in patients was less than in controls (p < 0.0001). As most of the cases investigated in this study were in their early stages, it can be concluded that reduced IL-17, IL-6, and TGF-β can be used as predictors for clinical stage and prognosis of cancers such as breast carcinoma.

J Neuroimmunol. 2015 Aug 15;285:125-8. doi: 10.1016/j.jneuroim.2015.05.022. Epub 2015 Jun 12.

Effect of high dose vitamin D intake on interleukin-17 levels in multiple sclerosis: A randomized, double-blind, placebo-controlled clinical trial

Toghianifar N1, Ashtari F2, Zarkesh-Esfahani SH3, Mansourian M4.

Author information

  • 1Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: n.toghiani@gmail.com.

  • 2Isfahan University of Medical Sciences, Isfahan, Iran; Isfahan Neuroscience Research Centre, Iran.

  • 3University of Isfahan, Department of Biology, Isfahan, Iran.

  • 4Department of Biostatistics and Epidemiology, Health School, Isfahan University of Medical Sciences, Isfahan, Iran.

Abstract

BACKGROUND:

Vitamin D has immunomodulatory effects in multiple sclerosis (MS). Vitamin D acts through various mechanisms such as secretion of cytokines. Interleukin-17 (IL-17) is a critical interleukin in inflammatory response in MS.

OBJECTIVE:

This study assessed the effect of oral high dose vitamin D intake on IL-17 levels in MS patients in a double blind randomized clinical trial.

METHODS:

94 patients with a diagnosis of relapsing remitting multiple sclerosis (RRMS) were randomized to two groups. One group received 50,000 IU vitamin D3 every five days for 12 weeks. The other group was given placebo. Both groups received interferon-β (IFN-β) treatment. Serum levels of IL-17 were measured at the beginning of the study and after 12weeks.

RESULTS:

IL-17 serum levels were 56.75±28.72pg/ml and 30.31±75.85pg/ml in the intervention and placebo group at the beginning of the study, respectively (Median±IQR, p=0.338). After 12weeks, IL-17 levels were 58.93±67.93pg/ml and 46.13±94.70pg/ml in the intervention and placebo group, respectively (Median±IQR, p=0.960). The multiple linear regression analysis indicated that the consumption of vitamin D3 was positively and significantly associated with the logarithm of IL-17 measures (β=1.719; p=0.002 and R2=0.91), adjusted by EDSS scores.

CONCLUSION:

IL-17 levels showed significant change in RRMS patients after receiving high dose vitamin D3 for 12 weeks.

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