IL17A

Official Full Name

interleukin 17A

Organism

Homo sapiens

GeneID

3605

Background

This gene is a member of the IL-17 receptor family which includes five members (IL-17RA-E) and the encoded protein is a proinflammatory cytokine produced by activated T cells. IL-17A-mediated downstream pathways induce the production of inflammatory molecules, chemokines, antimicrobial peptides, and remodeling proteins. The encoded protein elicits crucial impacts on host defense, cell trafficking, immune modulation, and tissue repair, with a key role in the induction of innate immune defenses. This cytokine stimulates non-hematopoietic cells and promotes chemokine production thereby attracting myeloid cells to inflammatory sites. This cytokine also regulates the activities of NF-kappaB and mitogen-activated protein kinases and can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO). IL-17A plays a pivotal role in various infectious diseases, inflammatory and autoimmune disorders, and cancer. High levels of this cytokine are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis. The lung damage induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is to a large extent, a result of the inflammatory response promoted by cytokines such as IL17A. [provided by RefSeq, Sep 2020]

Synonyms

IL17; CTLA8; IL-17; ILA17; CTLA-8; IL-17A;

Bio Chemical Class

Cytokine: interleukin

Protein Sequence

MTPGKTSLVSLLLLLSLEAIVKAGITIPRNPGCPNSEDKNFPRTVMVNLNIHNRNTNTNPKRSSDYYNRSTSPWNLHRNEDPERYPSVIWEAKCRHLGCINADGNVDYHMNSVPIQQEILVLRREPPHCPNSFRLEKILVSVGCTCVTPIVHHVA

Open

Disease

Acne vulgaris, Asthma, Multiple myeloma, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Solid tumour/cancer

Approved Drug

3 +

Clinical Trial Drug

8 +

Discontinued Drug

2 +

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Detailed Information

Interleukin-17A (IL-17A), the most known member in IL-17 family, is secreted by helper T cells (Th17), CD8 positive T cells, neutrophils, γδT cells, eosinophils, monocytes and NK cells. It has been shown that IL-17A plays key roles in inflammation, autoimmune diseases and host defense.

IL-17A signaling pathway

IL-17A is found to exert pleiotropic biological functions via several signaling cascades (Figure 1). Act1 is demonstrated to be a predominant effector which mediates intracellular signal transduction from IL-17RA. Upon the binding of IL-17A to IL-17RA/IL-17RC on the cytomembrane, effect factor Act1 is recruitment to receptor complex, then activating a number of signaling cascades including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and mitogen-activated protein kinase (MAPK) pathways. It has been shown that TNF receptor associated factor 6 (TRAF6) is recruited by Act1 through the TRAF interaction domains and then ubiquitinated by its U-box E3 ligase domain. Ubiquitinated TRAF6 activates NF-κB pathway via activating TGF β-activated kinase 1 (TAK1), phosphorylating IκB kinase (IKK) and phosphorylating IκBα. Finally, NF-κB enters to the nucleus to induce the transcription of numerous gene products directly involved in immune function. Extracellular regulated protein kinases (ERK) pathway is another Act1-dependent signal cascade and activated by its U-box E3 ligase activity. Studies have found that IL-17A induce the activation of ERK in various cells such as epithelial cells, chondrocytes, fibroblasts, stem cells, and nerve cells. Moreover, MAPK pathway is involved in IL-17A signal via p38. Additionally, IL-17A also effects on the stabilization of mRNA stabilization through forming a multi-protein complex with TRAF2, TRAF5, and arginine/serine-rich splicing factor (ASF). This complex is found to prevent the cleavage of mRNA from ASF and recruit the mRNA stabilizing factor HuR. Together, all the pathways mediate the biological functions of IL-17A.

IL-17A Figure 1. The signaling pathways of IL-17A.

IL-17A and tumor

Recently, a number of studies have indicated that IL-17A is involved in tumor hematogenous metastasis, lymphatic metastasis, local invasion and transcoelomic metastasis. It has been shown that IL-17A can act on the activation of signal transducers and activators of transcription (STAT3) via up-regulating vascular endothelial growth factor (VEGF), then promoting tumor angiogenesis, proliferation and metastasis. Moreover, several reports have demonstrated that IL-17A is contributed to lymphangiogenesis in tumor metastasis via up-regulating lymphangiogenic factors such as VEGF-C, VEGF-D and VEGF-A. For example, stimulation of IL-17A can significantly increase the expression of VEGF-C and VEGF-D in lung cancer. Additionally, studies showed that IL-17A accelerates the invasion of HCC through inducing the secretion of several pro-invasive factors. IL-17 is found to promote tumor cell invasion via Akt pathway, which induces the expression of IL-6. IL-6, then, acts on JAK2/STAT3 pathway and enhances the expression of pro-invasive factors, such as IL-8, Matrix metalloproteinases 2 (MMP-2) and VEGF. As for transcoelomic metastasis, previous studies have found that IL-17A might promote it via regulating the activation and production of MMPs and /or act on the adipocytes, which bear IL-17A receptors and secret cytokine like IL-6.

In addition, IL-17A is found to play dual face in several infections. On the one hand, IL-17A recruits neutrophils and induces the production of anti-microbial peptides, chemokines, and cytokines to limit pathogenesis after infection with pathogens. On the other hand, this pathway can lead to excessive inflammation and exacerbated pathology in the context of excessive inflammation and exacerbated pathology. Thus, it is required more attention when designing therapeutic strategies targeting to IL-17A.

References:

Monin L, et al. Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications. Cold Spring Harbor Perspectives in Biology, 2017, 10(4): a028522.
Chen K, et al. Interluekin-17a (il17a). Gene, 2017, 614: 8-14.
Wong H, et al. Maternal IL-17A in autism. Experimental Neurology, 2017, 299(Pt A).
Qian X, et al. Interleukin-17 acts as double-edged sword in anti-tumor immunity and tumorigenesis. Cytokine, 2017, 89(6):34-44.
Xu L L, et al. The mechanisms of IL-17A on promoting tumor metastasis. International Reviews of Immunology, 2017, 36(6):360.
Das S, et al. Yin and yang of interleukin-17 in host immunity to infection. F1000Research, 2017, 6.

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