User:Sindija Smite/IL-17C

Interleukin-17C, also known as CX2, is a protein that in humans is encoded by the IL17C gene. It is one of the cytokines of the IL-17 family. IL-17C functions in an autocrine manner, binding to a receptor complex consisting of two receptors - IL-17RA and IL-17RE, which are expressed on tissue epithelial cells and Th17 cells. Adaptor protein Act1 is essential for IL-17C signaling, ensuring successful NF-kappa-B inhibitor zeta (IκBζ) induction in Th17 cells, necessary for their proliferation.

Discovery
Both IL-17B and IL-17C were discovered in year 2000 by using the Basic Local Alignment Search Tool (BLAST) to look for encoded amino acid sequences similar to IL-17A. By the time its receptor remained unknown, but in 2011 the receptor was found to be heterodimer IL-17RA and IL-17RE.

Expression
IL-17C in humans mostly is produced by non-immune cells such as colonic and lung epithelial cells, keratinocytes and smooth muscle cells, like vascular smooth muscle cells.

In keratinocytes, IL-17C expression can be induced by such bacterial products as flagellin and peptidoglycan or cytokines like tumor necrosis factor-α. In colon epithelial cells, the production of IL-17C can be upregulated by agonists of the TLR2 or by proinflammatory cytokines (TNF-α and IL-1β). In normal human bronchial epithelial cells, the cytokine IL-1β stimulates IL-17C production, but IL-13, a cytokine produced by Th2 cells, suppresses it. It has been shown that TNF-α-mediated IL-17C induction in human keratinocytes is regulated by an NF-κB-dependent mechanism. In colonic epithelial cells and keratinocytes, IL-17 signaling leads to induction of chemokines and proinflammatory cytokines such as Cxcl1, Cxcl2, Ccl20, TNF, and IL-1β.

Function
In the epithelium, IL-17C maintains an autocrine loop that reinforces innate immune barriers while also stimulating inflammatory Th17 cells.

IL-17C is recognized to play a role in mucosal immunity of host defence against pathogens, especially bacteria. In acute Pseudomonas aeruginosa lung infection, L-17A-mediated production of IL-17C increases chemokine expression and neutrophil recruitment. Staphylococcus aureus-induced IL-17C expression in keratinocytes is mediated by the Pattern Recognition Receptor NOD2.

The IL-17C/RE axis has been implicated in the pathogenesis of a variety of disorders, including viral and autoimmune diseases, as well as cancer development and progression. One of the examples is psoriasis, where in comparison to nonlesional psoriatic skin, lesional psoriatic skin had higher IL-17C mRNA expression, as well as higher protein accumulation. In addition, in atopic dermatitis patients, IL-17C protein levels in keratinocytes were elevated when compared to healthy patients. The mRNA of IL-17C is also increased in synovial fluid mononuclear cells from patients with rheumatoid arthritis. In the mice model of collagen-induced arthritis, the disease can be exacerbated by IL-17C, which is linked to increased TNF and IL-6 production by macrophages.

This cytokine is also involved in some cardiovascular diseases. Smooth muscle cell–derived IL-17C plays a proatherogenic role by supporting the recruitment of Th17 cells to atherosclerotic lesions.

As a drug target
MOR106 is a human class IgG antibody that selectively binds both human and mouse IL-17C and neutralizes its function. It is specific to IL-17C and does not bind to other IL-17 family members. After successfully being tested in three different animal models of skin inflammation, MOR106 antibody was taken to the clinical trials. MOR106 is the world's first human monoclonal antibody directed against IL-17C that has been used in clinical trials. MOR106 has been tested in two phase-2 clinical studies, IGUANA and GECKO, for atopic dermatitis treatment. These studies have been terminated for futility.

In animals
In animals, IL-17C has similar involvement in immune regulation as in humans. F4+ Enterotoxigenic Escherichia coli (ETEC) can cause post-weaning diarrhea (PWD) in piglets. IL-17C is highly expressed in their intestinal epithelium and after infection with F4+ ETEC, the induction of IL-17C mRNA and protein expression in intestinal tissue has been observed. It is mediated by TRL5 signalling. As a result of this IL-17C expression, there is also an increased expression of antimicrobial peptides, showing a mucosal host defence response.

Also in lower vertebrates, IL-17C has an antimicrobial role. Transcription factors RORα and RORγ are expressed in a variety of cell types and are involved in the regulation of different inflammatory responses and differentiation of Th17 cell lineage, respectively. They are also to be found in Half-smooth tongue sole Cynoglossus semilaevis. After infection of C. semilaevis with V. Harveyi, the mRNA transcripts of the RORα and RORγ were significantly upregulated in the spleen and kidneys. Subsequently, RORα upregulation had an effect on IL-17 family members - upregulation of IL-17C, IL-17D and IL-17F -, but for RORγ upregulation of IL-17C and IL-17F.