IL17C - interleukin 17C |Elisa - Clia - Antibody - Protein

Background

Interleukin 17C (IL-17C) is a member of the IL-17 cytokine family, which is heavily involved in immune responses, particularly in inflammatory and autoimmune processes. The IL-17 family includes six members: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F, all of which contribute in varying ways to host defense, primarily by inducing inflammatory responses. IL-17C plays a distinct role in mucosal immunity, primarily by acting as a mediator of the host defense against bacterial pathogens, particularly at epithelial barriers.

IL-17C has drawn interest because of its autocrine and paracrine signaling capabilities, meaning that it can act both on the cells that produce it (autocrine signaling) and on neighboring cells (paracrine signaling). In contrast to IL-17A and IL-17F, which are secreted by Th17 cells, IL-17C is predominantly produced by epithelial cells. Its role in enhancing the immune response to infection makes it critical for barrier defense in tissues like the skin, lungs, intestines, and other mucosal surfaces. Dysregulation of IL-17C has been linked to several inflammatory diseases, including inflammatory bowel disease (IBD), psoriasis, and chronic inflammatory lung conditions.

Protein Structure

IL-17C shares structural similarities with other members of the IL-17 family, which are characterized by their four-helix bundle topology.

• Amino Acid Sequence: IL-17C is a small protein composed of 197 amino acids with a molecular weight of approximately 22 kDa. This size is consistent with other cytokines, allowing IL-17C to act as a soluble molecule capable of diffusing and interacting with specific receptors on neighboring cells.
• Secondary and Tertiary Structure: The defining feature of IL-17C, like other IL-17 cytokines, is its four-helix bundle. This structure is crucial for maintaining protein stability and enabling proper receptor binding. The helices are arranged in a compact, globular shape, which facilitates interaction with specific receptors.
• Homodimerization: Like other IL-17 cytokines, IL-17C is thought to form disulfide-linked homodimers. This homodimerization is necessary for its biological activity, as it enhances the cytokine's stability and its ability to bind to receptors.
• Receptor Binding Domains: IL-17C interacts with IL-17RE and IL-17RA receptors to exert its effects. These receptors are expressed on epithelial and immune cells. The receptor-binding region of IL-17C is critical for initiating signaling pathways, such as NF-κB and MAPK, that lead to the production of downstream inflammatory cytokines and antimicrobial peptides.
• Post-Translational Modifications: While specific post-translational modifications (PTMs) of IL-17C, such as glycosylation or phosphorylation, have not been extensively characterized, these modifications are common in cytokines and are essential for their function, stability, and interaction with receptors. PTMs can also regulate cytokine secretion and bioavailability.

Classification and Subtypes

IL-17C is classified within the IL-17 cytokine family, alongside other pro-inflammatory cytokines such as IL-17A, IL-17B, IL-17D, IL-17E (IL-25), and IL-17F. These cytokines share common structural features, including the four-helix bundle configuration and the ability to form homodimers or heterodimers. Despite these similarities, IL-17 family members have different receptor specificities and functions.

• IL-17 Family Overview:
• IL-17A and IL-17F: Primarily involved in autoimmune and inflammatory diseases, including rheumatoid arthritis and psoriasis.
• IL-17B: Implicated in chronic inflammation and some cancers.
• IL-17E (IL-25): Promotes Th2-type immune responses, contributing to allergy and asthma.
• IL-17D: The least studied member, thought to contribute to immune regulation.

IL-17C is unique within the IL-17 family in that it is produced by epithelial cells rather than immune cells, positioning it as a central player in barrier defense.

Function and Biological Significance

IL-17C is primarily involved in innate immune responses and plays a critical role in maintaining epithelial homeostasis and defending against bacterial infections at mucosal surfaces. Its functions are distinct from IL-17A and IL-17F, which are more focused on recruiting immune cells to inflamed tissues.

Functions:

1. Mucosal Immunity and Barrier Defense: IL-17C is a key cytokine in epithelial cell defense. It is produced in response to bacterial infections and other stress signals by epithelial cells in tissues such as the skin, lungs, and intestines. Once secreted, IL-17C acts in an autocrine or paracrine manner, promoting the production of antimicrobial peptides (AMPs) such as defensins and S100 proteins, which help to clear pathogens.
2. Inflammation: By interacting with the IL-17RE/IL-17RA receptor complex, IL-17C induces inflammatory responses in epithelial cells, leading to the secretion of pro-inflammatory cytokines (e.g., TNF-α, IL-6) and chemokines (e.g., CXCL1, CXCL8) that recruit immune cells, including neutrophils and macrophages, to the site of infection or damage. This cytokine cascade amplifies the immune response and helps to eliminate pathogens.
3. Tissue Homeostasis: In addition to its role in inflammation, IL-17C contributes to maintaining epithelial barrier integrity. By promoting the secretion of antimicrobial peptides and pro-inflammatory cytokines, IL-17C helps ensure that epithelial tissues can effectively respond to external challenges such as infection, damage, or dysbiosis.
4. Autocrine Signaling: IL-17C’s ability to signal in an autocrine manner (i.e., to act on the same cells that produce it) is unique among the IL-17 family. This allows epithelial cells to directly respond to bacterial stimuli by producing IL-17C and then stimulating their own production of defensive molecules without requiring the involvement of immune cells. This rapid response is essential for the immediate protection of barrier tissues.

Biological Significance:

IL-17C plays a pivotal role in innate immunity and barrier defense, particularly at epithelial surfaces. It provides a first line of defense against bacterial pathogens, working in conjunction with other cytokines and immune mediators to prevent the invasion of pathogens. In addition, IL-17C helps to maintain tissue homeostasis by promoting a controlled inflammatory response that resolves once the infection is cleared.

Unlike IL-17A and IL-17F, which are central to the development of autoimmune diseases through their interaction with immune cells, IL-17C primarily influences the behavior of epithelial cells and acts as a critical player in mucosal immunity. However, its overexpression or dysregulation can contribute to the pathology of chronic inflammatory diseases.

Clinical Issues

The dysregulation of IL-17C has been implicated in various inflammatory and autoimmune diseases, as well as in the development of some cancers. In these contexts, IL-17C's pro-inflammatory properties contribute to disease progression by exacerbating local tissue inflammation.

Diseases Associated with IL-17C:

1. Psoriasis: IL-17C is highly expressed in psoriatic skin lesions and is thought to contribute to the chronic inflammation observed in psoriasis. It drives the expression of other pro-inflammatory cytokines and promotes the infiltration of immune cells into the skin, leading to the characteristic thickened, inflamed skin patches associated with the disease.
2. Inflammatory Bowel Disease (IBD): Elevated levels of IL-17C have been detected in the intestinal mucosa of patients with Crohn's disease and ulcerative colitis, suggesting that it plays a role in maintaining the chronic inflammation characteristic of these conditions. By promoting the production of antimicrobial peptides and pro-inflammatory cytokines, IL-17C contributes to the dysregulated immune response observed in IBD.
3. Chronic Inflammatory Lung Diseases: IL-17C is expressed in the lungs and has been implicated in conditions such as asthma and chronic obstructive pulmonary disease (COPD). In these diseases, IL-17C promotes airway inflammation and remodeling, contributing to symptoms such as airway hyperreactivity and mucus production.
4. Cancer: IL-17C has been linked to tumor progression, particularly in cancers of epithelial origin, such as colorectal cancer. IL-17C may promote tumor growth by inducing local inflammation and creating a microenvironment that supports cancer cell proliferation and survival.

Therapeutic Potential:

Targeting the IL-17C/IL-17RE/IL-17RA axis is a potential strategy for treating diseases characterized by chronic epithelial inflammation. Given IL-17C’s role in diseases like psoriasis, IBD, and asthma, therapies aimed at blocking IL-17C or its receptors could help reduce inflammation and improve clinical outcomes. IL-17 inhibitors are already in use for treating psoriasis, and similar approaches could be extended to diseases driven by IL-17C.

Summary

IL-17C is a key cytokine involved in epithelial defense and mucosal immunity. Unlike other IL-17 family members that are produced by immune cells, IL-17C is primarily secreted by epithelial cells, where it helps to defend against bacterial infections and maintain tissue homeostasis. However, its dysregulation can contribute to the development of chronic inflammatory diseases and certain cancers. Targeting IL-17C may offer new therapeutic opportunities for treating conditions characterized by excessive inflammation at epithelial barriers.