Introduction to the IL-17 Family: Unraveling the Signaling Pathways and Functions
IL-17 Family Proteins
The IL-17 family encompasses a group of cytokines that play diverse roles in immune responses and inflammation. The IL-17A protein, initially known as CTLA-8, was the first discovered member of this family, cloned from rodent-activated hybridoma T cells in 1993. With a total of 177 amino acids, IL-17A forms two pairs of antiparallel β-sheets and maintains its structural stability through multiple disulfide bonds. In addition to IL-17A, the IL-17 family comprises five other members: IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F. Among them, IL-17F shares the highest similarity (55%) with IL-17A and is frequently co-expressed with it, while IL-17E exhibits the lowest similarity of approximately 17%.
IL-17 Receptor Family
In 1995, the receptor (IL-17R) for IL-17 proteins was discovered, and the receptor family consists of five members designated as IL-17RA to IL-17RE. IL-17R is a transmembrane protein with two fibronectin III-like domains (FN domains) located outside the cell membrane, responsible for mediating ligand-receptor binding. At the C-terminal region of the cell membrane, a conserved sequence called SEFIR defines the IL-17R family as a novel cytokine receptor family. Notably, IL-17R recruits Act-1 protein (also known as CIKS) to initiate intracellular signal transduction. The recruitment of IL-17R subsequently triggers downstream cascade signaling pathways.
IL-17A: The Prototypical Member Shaping Inflammatory Responses
IL-17A stands as the quintessential and pivotal member within the IL-17 family. Primarily synthesized by T cells, particularly CD4+ Th17 cells, IL-17A plays a critical role in the onset and progression of diverse inflammatory responses and autoimmune diseases. It exerts its influence by fostering the infiltration and activation of inflammatory cells, thereby stimulating essential host defense mechanisms. Moreover, IL-17A possesses the ability to induce epithelial cells to generate a plethora of inflammatory mediators, actively participating in the orchestration of inflammatory reactions and tissue damage.
Diverse Functions of the IL-17 Family: Beyond IL-17A
The IL-17 family encompasses an array of members, including IL-17B, IL-17C, IL-17D, and IL-17F, which possess significant roles in immune regulation and inflammatory responses. These members actively participate in the activation of immune cells, production of inflammatory mediators, and facilitate processes such as immune cell proliferation and tissue repair.
Furthermore, IL-17 family members exhibit binding affinity towards specific receptors, triggering downstream signaling pathways that regulate immune cell functions and immune responses. Their pivotal involvement extends to a wide range of inflammatory diseases, autoimmune conditions, and tumors, making them prime targets for the development of therapeutic strategies. Notably, anti-IL-17A drugs have been successfully developed, yielding remarkable clinical outcomes in the treatment of autoimmune diseases like rheumatoid arthritis and psoriasis. Ongoing research and development endeavors promise to further broaden the scope of applications within the IL-17 family, offering patients novel treatment options and renewed hope.
Research Areas of the IL-17 Family
The IL-17 family encompasses diverse research fields, with significant contributions in various areas. The following highlights some important research domains:
1. Immune Regulation and Inflammation
IL-17 family molecules hold a crucial role in immune regulation and inflammation. They actively promote inflammatory responses, facilitate the recruitment and activation of inflammatory cells, and contribute to the development and progression of immune-related diseases like autoimmune disorders, allergic reactions, and infections. Researchers strive to unravel the intricate mechanisms underlying the immune regulatory and inflammatory functions of the IL-17 family, with a focus on exploring their potential applications in treating related diseases.
2. Autoimmune Diseases
The IL-17 family plays a pivotal role in various autoimmune diseases. For instance, IL-17A and IL-17F exhibit significant involvement in conditions like psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Researchers delve into deciphering the specific mechanisms by which the IL-17 family influences autoimmune diseases, aiming to develop targeted therapeutics directed at IL-17 family molecules.
The IL-17 family also emerges as a critical player in cancer. It regulates the tumor microenvironment, impacting tumor growth, invasion, metastasis, and even tumor immune evasion. Researchers diligently investigate the intricate mechanisms underlying the role of IL-17 family molecules in cancer, paving the way for potential therapeutic strategies targeting this pathway.
4. Infection and Immune Defense
IL-17 family molecules play a vital role in infection and immune defense. They actively participate in antimicrobial immune responses, modulate inflammatory reactions, and contribute to mucosal immunity. Researchers devote their efforts to comprehensively understanding the precise mechanisms through which IL-17 family molecules operate in infection and immune defense, envisioning their potential applications in the prevention and treatment of related diseases.
 Gu, C. , Wu, L. , & Li, X. . (2013). Il-17 family: cytokines, receptors and signaling. Cytokine, 64(2), 477-485.