IL17F - interleukin 17F |Elisa - Clia - Antibody - Protein

Background

Interleukin-17F (IL-17F) is a member of the IL-17 cytokine family, which plays a pivotal role in regulating inflammatory responses and bridging the innate and adaptive immune systems. IL-17F is closely related to IL-17A, the founding member of the family, and shares functional similarities with it. Both IL-17F and IL-17A are secreted primarily by T-helper 17 (Th17) cells, a subset of CD4+ T-cells involved in immunity against extracellular pathogens, especially fungi and bacteria. In addition to Th17 cells, IL-17F can also be produced by other cell types such as natural killer (NK) cells, innate lymphoid cells (ILCs), and neutrophils.

IL-17F is implicated in several immune-mediated processes, including the promotion of inflammation in tissues. It is primarily associated with the pathogenesis of autoimmune diseases such as psoriasis, asthma, and inflammatory bowel disease (IBD). While IL-17F shares many similarities with IL-17A, its expression and function are somewhat distinct, providing specific inflammatory signals in certain tissues and conditions.

Protein Structure

IL-17F is a glycoprotein composed of 153 amino acids with a molecular weight of approximately 20-25 kDa. It shares about 50% sequence homology with IL-17A and is structurally similar to other members of the IL-17 family.

• Homodimer and Heterodimer Formation: IL-17F can exist in two different forms:

1. Homodimer (IL-17F/F): IL-17F can form homodimers by pairing with another IL-17F monomer. This form is predominantly secreted by Th17 cells.
2. Heterodimer (IL-17A/F): IL-17F can also heterodimerize with IL-17A to form the IL-17A/F heterodimer. This heterodimer has overlapping but distinct functions compared to the homodimers of IL-17A or IL-17F.

• Structural Features:
• IL-17F, like IL-17A, adopts a cystine knot fold, a conserved structural motif seen in the IL-17 cytokine family. This structure is stabilized by disulfide bonds between conserved cysteine residues, which help maintain the stability and functionality of the protein.
• The four-helix bundle structure, typical of the IL-17 family, is a key feature that facilitates receptor binding and activation of downstream signaling pathways.
• Receptor Interaction: IL-17F primarily signals through the IL-17 receptor complex, consisting of IL-17RA and IL-17RC. The receptor complex is essential for triggering downstream immune responses, including the induction of pro-inflammatory cytokines and chemokines. The IL-17A/F heterodimer binds to the same receptor complex but with differing affinities, leading to distinct signaling outcomes.

Classification and Subtypes

IL-17F is classified within the IL-17 cytokine family, which consists of six members: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F. This family plays critical roles in inflammation, host defense, and immune regulation.

• IL-17F/F (Homodimer): The most common form, produced predominantly by Th17 cells, triggers strong inflammatory responses by activating the IL-17RA/IL-17RC receptor complex.
• IL-17A/F (Heterodimer): A hybrid of IL-17A and IL-17F, this form shares receptor usage with IL-17F/F but may lead to different signaling dynamics and cellular responses.

Though IL-17F does not have specific subtypes, the existence of both homodimers and heterodimers with IL-17A gives it distinct functional versatility within the immune system.

Function and Biological Significance

IL-17F plays a crucial role in orchestrating the immune response against extracellular pathogens, particularly bacteria and fungi. It acts primarily by promoting inflammation and recruiting neutrophils and other immune cells to sites of infection or tissue damage. However, IL-17F is also implicated in autoimmune diseases and chronic inflammatory conditions due to its potent pro-inflammatory properties.

Key Functions:

1. Induction of Pro-inflammatory Cytokines: IL-17F stimulates the production of a wide array of pro-inflammatory cytokines and chemokines, including IL-6, TNF-α, GM-CSF, CXCL1, CXCL8 (IL-8), and CCL2 (MCP-1). These molecules play critical roles in recruiting neutrophils and monocytes to inflamed tissues and initiating immune responses.
2. Mucosal Defense and Epithelial Protection: IL-17F is important in protecting mucosal surfaces from microbial invasion, particularly in the respiratory and gastrointestinal tracts. By inducing antimicrobial peptides such as defensins and S100 proteins, IL-17F contributes to the elimination of pathogens at barrier surfaces.
3. Neutrophil Recruitment: One of the most significant roles of IL-17F is the recruitment of neutrophils to sites of infection or tissue damage. Neutrophils are key players in the early stages of immune responses and are essential for clearing bacterial and fungal pathogens.
4. Amplification of Inflammatory Responses: IL-17F functions synergistically with other cytokines, including IL-1β and TNF-α, to amplify inflammatory responses. This cytokine crosstalk enhances the immune system’s ability to respond to infections, but it can also lead to chronic inflammation and tissue damage in autoimmune diseases.

Clinical Issues

Given its potent inflammatory properties, IL-17F has been implicated in several chronic inflammatory and autoimmune diseases, including:

Diseases Associated with IL-17F:

1. Psoriasis: Both IL-17F and IL-17A are elevated in psoriatic skin lesions, and their activity drives the hyperproliferation of keratinocytes and the recruitment of neutrophils. IL-17F is a key mediator in the pathogenesis of psoriasis, contributing to the chronic inflammation seen in this disease.
2. Asthma and Allergic Diseases: IL-17F has been found to play a role in asthma by inducing airway inflammation, mucus production, and hyperresponsiveness. Elevated levels of IL-17F are associated with severe asthma and correlate with disease severity.
3. Inflammatory Bowel Disease (IBD): In Crohn's disease and ulcerative colitis, IL-17F is involved in promoting chronic intestinal inflammation. It induces the production of pro-inflammatory cytokines and chemokines in the intestinal epithelium, contributing to the tissue damage and inflammation characteristic of IBD.
4. Rheumatoid Arthritis (RA): In RA, IL-17F is elevated in the synovial fluid of affected joints. Its role in inducing inflammation and recruiting immune cells contributes to the chronic joint inflammation and tissue destruction observed in RA patients.

Therapeutic Implications:

Therapies targeting IL-17F, often in combination with IL-17A, have emerged as promising treatments for autoimmune diseases. For instance, biologics such as secukinumab and ixekizumab, which target IL-17A and IL-17F, have demonstrated efficacy in reducing inflammation and improving clinical outcomes in diseases like psoriasis and psoriatic arthritis. These therapies work by inhibiting the binding of IL-17A/F and IL-17F/F to their receptors, thereby reducing downstream inflammatory signaling.

Summary

IL-17F is a pro-inflammatory cytokine that plays a critical role in the immune system, particularly in mucosal defense, neutrophil recruitment, and inflammatory responses. It shares significant structural and functional similarities with IL-17A but has distinct roles in promoting inflammation, especially in the context of autoimmune diseases like psoriasis, asthma, and IBD. IL-17F induces the production of a wide range of inflammatory cytokines and chemokines, contributing to the immune system's ability to clear infections, but also driving chronic inflammation in autoimmune disorders.

Clinically, IL-17F is an important target for the treatment of inflammatory diseases. The development of biologics that inhibit IL-17F activity has demonstrated success in reducing disease severity in psoriasis and other autoimmune conditions. Overall, IL-17F is a critical player in both protective immune responses and pathological inflammation, making it a significant cytokine in immunology and therapeutic development.