IL-17 Family
Available Resources for the Study of IL-17 Family
At Creative BioMart, our primary focus revolves around advancing research within the realm of the IL-17 family. With steadfast commitment, we aim to equip scientists with cutting-edge tools and expertise pertaining to IL-17 family receptors, ligands, and signaling molecules.
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- Furthermore, we furnish a wealth of valuable resources to bolster research endeavors within the IL-17 family. These resources encompass pathways, protein functions, interacting proteins, and other pertinent resources, significantly enhancing research outcomes and impact.
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About IL-17 Family
The IL-17 family is a group of cytokines that play important roles in immune responses, inflammation, and host defense. The family consists of six members: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F. These cytokines exhibit overlapping, yet distinct, functions and act through specific receptors and downstream signaling molecules.
IL-17A
- IL-17A is the most well-studied member of the IL-17 family.
- It is primarily produced by T helper 17 (Th17) cells, γδ T cells, and innate lymphoid cells (ILCs).
- IL-17A acts through the IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC) complexes.
- Downstream signaling involves the recruitment of the adaptor protein Act1 (CIKS), which activates NF-κB and MAPK signaling pathways.
IL-17B
- IL-17B is produced by various cell types, including T cells, macrophages, and epithelial cells.
- It signals through the IL-17 receptor B (IL-17RB) and IL-17 receptor D (IL-17RD) complexes.
- IL-17RB, along with IL-17RA or IL-17RD, activates downstream signaling pathways, such as NF-κB and MAPK.
IL-17C
- IL-17C is mainly produced by epithelial cells, particularly in mucosal tissues.
- It signals through the IL-17RA and IL-17RE receptor complexes.
- IL-17C binding to its receptors triggers Act1-dependent signaling, leading to NF-κB activation.
IL-17D
- IL-17D is produced in various tissues, including the skin, lung, and lymphoid organs.
- It can activate the IL-17RA and IL-17RD receptor complex.
- The downstream signaling mechanisms of IL-17D are not yet fully understood.
IL-17E (IL-25)
- IL-17E is primarily produced by epithelial cells, including lung and intestinal epithelial cells.
- It signals through the IL-17RA and IL-17RB receptor complex.
- IL-17E activates downstream signaling pathways, such as STAT6 and MAPK, leading to the production of cytokines associated with allergic responses.
IL-17F
- IL-17F is structurally similar to IL-17A and is secreted by Th17 cells and other immune cells.
- It shares receptor usage with IL-17A and can bind to IL-17RA and IL-17RC.
- IL-17F signaling induces similar downstream pathways as IL-17A, including NF-κB and MAPK.
Common signaling molecules and pathways
- Act1 (CIKS): An adaptor protein that interacts with IL-17 receptors and mediates downstream signaling events, including NF-κB and MAPK activation.
- NF-κB: A transcription factor involved in the regulation of inflammation and immune responses.
- MAPK: Signaling pathways, including ERK, JNK, and p38, are involved in cellular responses, gene expression, and cytokine production.
Understanding the ligands, receptors, and signaling molecules associated with the IL-17 family is crucial for comprehending the complex mechanisms underlying immune responses, inflammation, and related diseases. Continued research on this family of cytokines provides insights into their roles in health and disease and may lead to the development of targeted therapies for various inflammatory and autoimmune disorders.
Fig.1 Interleukin-17 (IL-17) and IL-17 receptor family members and their biological roles. (Kirkham BW, et al., 2014)
Detailed Mechanism of IL-17 Family Signaling Pathway
The IL-17 family signaling pathway involves a series of molecular events that occur upon binding of IL-17 cytokines to their respective receptors. Here is a detailed mechanism of the IL-17 family signaling pathway:
Receptor Complex Formation
IL-17 family receptors typically form receptor complexes composed of multiple subunits. The specific composition of the receptor complex determines ligand specificity and downstream signaling. For example, IL-17RA forms homodimers or heterodimers with IL-17RC or IL-17RE. IL-17RB and IL-17RD also form heterodimeric receptor complexes with other subunits.
Act1 Recruitment
Upon ligand binding to the IL-17 receptor complex, an adaptor protein called Act1 (also known as CIKS) is recruited to the receptor complex. Act1 plays a crucial role in IL-17 receptor signaling by mediating downstream signaling events. Act1 contains multiple functional domains that enable its interaction with various signaling molecules.
TRAF6 Activation
Act1 interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), leading to the recruitment and activation of TRAF6. TRAF6 is an E3 ubiquitin ligase that can catalyze the attachment of ubiquitin molecules to target proteins.
Ubiquitination and TAK1 Activation
Activated TRAF6 promotes the ubiquitination of receptor complex components, including Act1 itself. This ubiquitination process helps to recruit and activate transforming growth factor-beta-activated kinase 1 (TAK1). TAK1 is a key kinase involved in IL-17 signaling.
IKK Complex Activation
TAK1, in association with TAK1-binding proteins (TAB1, TAB2, and TAB3), phosphorylates and activates the IκB kinase (IKK) complex. The IKK complex consists of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit called IKKγ (also known as NEMO).
IκBα Degradation and NF-κB Activation
Activated IKK phosphorylates the inhibitory protein IκBα, leading to its ubiquitination and subsequent proteasomal degradation. This results in the release of the nuclear factor-kappa B (NF-κB) proteins, such as p50 and p65, from the IκBα-NF-κB complex. The freed NF-κB proteins translocate into the nucleus, where they bind to specific DNA sequences and induce the transcription of genes involved in inflammation and immune responses.
MAPK Activation
IL-17 family signaling also activates mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. Act1 can interact with various components of the MAPK pathways, leading to their activation. These MAPK pathways regulate gene expression, cytokine production, and cell survival.
Induction of Cytokines and Chemokines
The activation of IL-17 family receptors and downstream signaling pathways results in the production of various pro-inflammatory cytokines and chemokines. These include interleukins (IL-6, IL-8), tumor necrosis factor-alpha (TNF-α), granulocyte-colony stimulating factor (G-CSF), and chemokine (C-X-C motif) ligand 1 (CXCL1). These molecules contribute to the recruitment and activation of immune cells, amplifying the inflammatory response.
Overall, the IL-17 family signaling pathway involves the recruitment and activation of Act1, which leads to the activation of TRAF6, TAK1, and the downstream NF-κB and MAPK signaling pathways. These signaling events ultimately regulate gene expression, cytokine production, and immune responses, playing a crucial role in inflammation and host defense.
Fig.2 Signaling pathway of Interleukin-17A (IL-17A). (Chen J, et al., 2020)
Creative BioMart is committed to helping you achieve your scientific goals and make meaningful contributions to the study of the mechanisms of action of the various components of the IL-17 family and their role in disease. Contact us today to learn more about our products and resources.
Related References:
- Kirkham BW, Kavanaugh A, Reich K. Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis. Immunology. 2014;141(2):133-142. doi:10.1111/imm.12142
- Chen J, Liu X, Zhong Y. Interleukin-17A: The Key Cytokine in Neurodegenerative Diseases. Front Aging Neurosci. 2020;12:566922. Published 2020 Sep 29. doi:10.3389/fnagi.2020.566922
