IL17F

Official Full Name

interleukin 17F

Organism

Homo sapiens

GeneID

112744

Background

The protein encoded by this gene is a cytokine that shares sequence similarity with IL17. This cytokine is expressed by activated T cells, and has been shown to stimulate the production of several other cytokines, including IL6, IL8, and CSF2/GM_CSF. This cytokine is also found to inhibit the angiogenesis of endothelial cells and induce endothelial cells to produce IL2, TGFB1/TGFB, and monocyte chemoattractant protein-1. [provided by RefSeq, Jul 2008]

Synonyms

ML1; ML-1; IL17A; CANDF6; IL-17F;

Bio Chemical Class

Cytokine: interleukin

Protein Sequence

MTVKTLHGPAMVKYLLLSILGLAFLSEAAARKIPKVGHTFFQKPESCPPVPGGSMKLDIGIINENQRVSMSRNIESRSTSPWNYTVTWDPNRYPSEVVQAQCRNLGCINAQGKEDISMNSVPIQQETLVVRRKHQGCSVSFQLEKVLVTVGCTCVTPVIHHVQ

Open

Disease

Psoriasis, Psoriatic arthritis

Approved Drug

1 +

Clinical Trial Drug

Discontinued Drug

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Detailed Information

IL17F (Interleukin-17F) belongs to the IL17 cytokine family and is a key pro-inflammatory molecule that plays a crucial role in maintaining host immune defense, tissue repair, the development of inflammatory diseases, and cancer progression. As a factor highly similar to IL17A in both structure and function, IL17F exhibits unique and irreplaceable biological effects in various physiological and pathological contexts.

Composition and Receptor Recognition

The IL17 family consists of six members (IL17A to IL17F), and their signaling relies on the IL17 receptor family (IL17RA to IL17RE). IL17F primarily binds by forming a heterodimeric complex with IL17RA and IL17RC receptors, initiating signal cascades. Although both IL17A and IL17F can activate downstream pathways through the same receptor complex, their binding affinity and bioactivity differ. Typically, IL17A exhibits higher activity, whereas IL17F plays complementary or independent roles in specific tissues and disease conditions.

Structural Characteristics

All members of the IL17 receptor family are single-pass transmembrane proteins containing fibronectin type III (FNIII) domains and a SEFIR (similar to TIR domain) segment. The TIR-like loop domain and C/EBPβ activation domain (CBAD) unique to IL17RA are critical for signal transduction. Upon binding to the IL17RA/IL17RC complex, IL17F induces downstream signaling, including the NF-κB and MAPK pathways, thereby regulating the expression of inflammatory cytokines, chemokines, and antimicrobial peptides.

Signaling Pathways and Regulatory Mechanisms

The IL17F signaling pathway shares similarities with the classical activation pattern of Toll-like receptors (TLRs) and IL-1 receptors (IL-1R) but also possesses unique features. After binding to its receptors, IL17F recruits the adaptor protein Act1, which further interacts with TRAF6 to activate the NF-κB and MAPK pathways, promoting the expression of inflammatory factors. Simultaneously, the Act1-TRAF2/5 complex enhances the stability and translational efficiency of target gene mRNAs, amplifying inflammatory signals at both transcriptional and post-transcriptional levels.

Figure 1. Common IL-17 signaling pathways. (Huangfu L, et al., 2023)

Clinical Research and Therapeutic Prospects

The role of IL17F in infection defense, autoimmune diseases, and tumor immunity has been gradually elucidated. Clinical studies indicate that IL17F overexpression is associated with various chronic inflammatory diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and asthma. In psoriasis patients, IL17F expression is significantly elevated and closely linked to inflammatory responses in lesional areas and keratinocyte activation. Small-molecule inhibitors and monoclonal antibodies targeting IL17F or its receptor complex are under development, with some IL17A/F dual-targeting therapies already in Phase III clinical trials for moderate-to-severe plaque psoriasis and other IL17-driven immune disorders.

Bimekizumab is a humanized IgG1 monoclonal antibody that simultaneously neutralizes IL17A and IL17F. Multiple Phase III clinical trials have demonstrated its superiority over placebo, ustekinumab, adalimumab, and secukinumab in treating moderate-to-severe plaque psoriasis, with rapid onset and favorable tolerability. Additionally, Bimekizumab has shown promising efficacy in treating psoriatic arthritis and ankylosing spondylitis.

Sonelokimab is a trivalent nanobody targeting IL17A and IL17F. Its half-life is extended due to its binding to human serum albumin. In a Phase IIb clinical trial, Sonelokimab demonstrated significant efficacy and safety in treating moderate-to-severe plaque psoriasis, notably improving PASI90 and PASI100 response rates.

Furthermore, in certain solid tumor studies, IL17F has been suggested to both promote chronic inflammation in the tumor microenvironment and exert anti-tumor effects by modulating immune cell recruitment. The specific mechanisms depend on the tumor type and microenvironment, indicating IL17F's potential value in future cancer immunotherapy development.

References

Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. 2023 Jan;23(1):38-54.
Huangfu L, Li R, Huang Y, et al. The IL-17 family in diseases: from bench to bedside. Signal Transduct Target Ther. 2023 Oct 11;8(1):402.

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