IL22 - interleukin 22 |Elisa - Clia - Antibody - Protein

Background

Interleukin 22 (IL-22) is a cytokine that belongs to the IL-10 family of cytokines. It plays a critical role in the innate and adaptive immune systems, particularly at epithelial barriers such as the skin, lungs, intestines, and liver. IL-22 is unique in that it primarily targets non-hematopoietic cells (e.g., epithelial cells) rather than immune cells. It promotes tissue protection, regeneration, and defense against pathogens, particularly in the context of infections and inflammatory diseases. IL-22 is primarily produced by a subset of CD4+ T cells, including Th17, Th22 cells, natural killer (NK) cells, and innate lymphoid cells (ILCs).

The role of IL-22 is highly context-dependent. While it contributes to maintaining epithelial integrity and promoting tissue repair, excessive or chronic IL-22 production can exacerbate inflammatory diseases, such as psoriasis, inflammatory bowel disease (IBD), and rheumatoid arthritis (RA). Its involvement in balancing tissue protection and inflammation highlights its significance in health and disease.

Protein Structure

IL-22 is a monomeric glycoprotein composed of 146 amino acids, with a molecular weight of approximately 19.5 kDa. Structurally, IL-22 is part of the IL-10 cytokine family, which also includes IL-10, IL-24, IL-26, and IL-28/IL-29 (IFN-lambda). Like other cytokines in this family, IL-22 adopts a typical four-α-helix bundle structure.

• Primary Structure: The IL-22 sequence contains six conserved cysteine residues that form three disulfide bonds, which are essential for stabilizing the three-dimensional structure.
• Secondary and Tertiary Structure: The four-helix bundle consists of long α-helices connected by loop regions. This structure is typical of the IL-10 family, providing stability and receptor-binding capability. The disulfide bonds further enhance the structural integrity of the protein.
• Receptor Interaction: IL-22 exerts its biological effects by binding to a heterodimeric receptor complex, composed of IL-22R1 and IL-10R2. Unlike many other cytokines, IL-22 does not act directly on immune cells but instead binds to receptors expressed on non-immune cells, particularly epithelial cells and fibroblasts in tissues such as the skin, liver, and intestines.
• Signaling Pathways: Upon binding to its receptor, IL-22 activates downstream signaling pathways, including the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, particularly STAT3, as well as the mitogen-activated protein kinase (MAPK) and PI3K-Akt pathways. These pathways regulate various cellular processes such as cell proliferation, survival, antimicrobial defense, and tissue repair.

Classification and Subtypes

IL-22 is classified as a member of the IL-10 family of cytokines, which are characterized by their ability to modulate immune responses and epithelial cell functions. Within the IL-22 cytokine family, no distinct subtypes of IL-22 exist, but it works in concert with other cytokines, such as IL-17 and IL-23, which share roles in mediating inflammation and tissue protection at epithelial barriers.

Receptor Complex:

• IL-22R1: A receptor chain specific for IL-22, mainly expressed on epithelial cells and not on immune cells.
• IL-10R2: A common receptor chain shared with IL-10 and other cytokines of the IL-10 family.

IL-22 also interacts with IL-22 binding protein (IL-22BP), a soluble receptor that can bind to IL-22, preventing it from signaling through its receptor. IL-22BP acts as a natural antagonist of IL-22 and plays a key role in regulating its activity in tissues.

Function and Biological Significance

IL-22 is a key player in maintaining epithelial integrity and supporting host defense at mucosal surfaces. Its effects are largely protective and regenerative, but in certain circumstances, IL-22 can contribute to pathological inflammation.

Major Functions:

Epithelial Cell Protection and Regeneration:

• IL-22 promotes epithelial cell proliferation and survival, especially after injury. It enhances tissue repair by stimulating the production of anti-apoptotic proteins and factors that support tissue regeneration.
• IL-22 induces the expression of antimicrobial peptides such as RegIIIγ and β-defensins, which play crucial roles in defending against bacterial infections, particularly at mucosal barriers like the gut and lungs.

Immune Defense:

• IL-22 helps maintain the integrity of mucosal barriers in the gut and skin, protecting these tissues from bacterial invasion. In the gut, for instance, IL-22 regulates the production of mucins and other factors that contribute to the physical barrier separating the microbiota from host tissues.
• IL-22 is essential in early responses to infections, particularly with extracellular pathogens. Its role in promoting the production of antimicrobial peptides and strengthening epithelial barriers makes it a key player in controlling infections, particularly in the lungs, intestines, and skin.

Inflammation and Autoimmunity:

• While IL-22 is protective in many contexts, it can also exacerbate chronic inflammation. In diseases such as psoriasis, overproduction of IL-22 leads to keratinocyte hyperproliferation and inflammation. Similarly, elevated levels of IL-22 contribute to gut inflammation in inflammatory bowel disease (IBD) and liver damage in autoimmune hepatitis.
• IL-22 is closely linked with IL-17, and the two cytokines often work together to promote inflammation at epithelial surfaces. IL-22’s role in driving epithelial proliferation and immune activation can sometimes lead to excessive tissue remodeling and pathological inflammation.

Tissue-Specific Effects:

• Skin: IL-22 plays a prominent role in skin conditions, including psoriasis and atopic dermatitis. In psoriasis, IL-22 drives keratinocyte proliferation and inflammatory responses, contributing to the thickened, scaly plaques characteristic of the disease.
• Liver: IL-22 is also involved in liver regeneration and can protect against liver damage during acute or chronic injury. However, in the context of chronic inflammation, IL-22 may promote fibrosis.
• Gut: In the gut, IL-22 regulates the production of antimicrobial peptides and promotes mucosal healing after damage. However, dysregulated IL-22 signaling can contribute to gut inflammation and exacerbate diseases like Crohn's disease.

Clinical Issues

IL-22 has been implicated in various diseases due to its dual role in tissue protection and inflammation. While it plays a protective role in tissue repair and pathogen defense, excessive or dysregulated IL-22 signaling can contribute to autoimmune diseases and chronic inflammatory conditions.

Diseases Associated with IL-22:

Psoriasis:

• IL-22 is highly elevated in the psoriatic lesions of patients with psoriasis, and it drives keratinocyte hyperproliferation and inflammation. IL-22, in concert with IL-17, contributes to the characteristic skin changes seen in psoriasis, including the development of thickened, scaly plaques.

Inflammatory Bowel Disease (IBD):

• In Crohn's disease and ulcerative colitis, elevated IL-22 levels have been linked to gut inflammation and epithelial damage. While IL-22 can promote mucosal healing, chronic production can exacerbate inflammatory responses, worsening disease severity.

Rheumatoid Arthritis (RA):

• IL-22 levels are elevated in the synovial fluid of patients with RA, where it contributes to joint inflammation and tissue damage. IL-22 promotes the production of pro-inflammatory cytokines and can exacerbate the destruction of joint tissues.

Liver Diseases:

• In the liver, IL-22 can have hepatoprotective effects, particularly during acute injury. However, chronic IL-22 production can contribute to fibrosis in conditions like autoimmune hepatitis and non-alcoholic fatty liver disease (NAFLD).

Therapeutic Potential:

IL-22 has emerged as a potential therapeutic target due to its role in autoimmune and inflammatory diseases. Therapies that modulate IL-22 activity could be beneficial for diseases like psoriasis, RA, and IBD. Additionally, given its role in promoting tissue regeneration, IL-22 is being explored for therapeutic applications in tissue repair and regeneration following injury.

• IL-22-Fc Fusion Proteins: IL-22-based therapies are being investigated for their ability to promote tissue regeneration in diseases such as acute liver failure or intestinal injury.

Summary

IL-22 is a critical cytokine that modulates epithelial barrier integrity, antimicrobial defense, and tissue repair. Its dual nature—both protective and inflammatory—makes it a key player in immune responses at mucosal surfaces. While IL-22 supports tissue regeneration and protects against pathogens, dysregulated IL-22 activity contributes to chronic inflammation and autoimmune diseases. Understanding the context-specific roles of IL-22 is essential for developing targeted therapies that harness its regenerative properties while mitigating its pro-inflammatory effects.