IL11 - interleukin 11 |Elisa - Clia - Antibody - Protein

Background

Interleukin-11 (IL-11) is a member of the IL-6-type cytokine family, which plays crucial roles in regulating immune responses, inflammation, and hematopoiesis. IL-11 was first identified for its role in promoting the proliferation of hematopoietic stem cells and megakaryocytes, which are essential for platelet production. Since then, IL-11 has been implicated in various biological processes, including tissue regeneration, bone remodeling, and immune system regulation. IL-11 signals through its specific receptor complex, initiating various downstream signaling cascades, primarily through the JAK/STAT pathway.

IL-11 is mainly secreted by stromal cells, fibroblasts, and epithelial cells in response to various stimuli, including inflammatory signals. While initially considered a supportive cytokine in hematopoiesis, more recent studies have shown that IL-11 plays a significant role in tissue fibrosis, chronic inflammation, and even cancer progression. Therefore, IL-11 is now recognized as a multifunctional cytokine with both protective and pathological roles in different physiological and pathological contexts.

Protein Structure

IL-11 is a relatively small cytokine with a molecular weight of approximately 19-23 kDa depending on the degree of glycosylation. It consists of a single polypeptide chain of 178 amino acids, but the mature, secreted form of IL-11 contains 178 amino acids after signal peptide cleavage.

Key structural features include:

• Four α-helix bundle: Like other members of the IL-6 cytokine family, IL-11 adopts a four α-helix bundle topology. These helices are arranged in an up-up-down-down configuration and are responsible for maintaining the protein's structural integrity.
• Disulfide bridges: IL-11 has two disulfide bridges that are crucial for the stabilization of its tertiary structure. These disulfide bonds are essential for maintaining the proper folding of IL-11, which is necessary for its biological activity.
• Glycosylation: IL-11 is glycosylated at multiple sites, which is essential for its stability and secretion. The glycosylation state can vary, contributing to the slight differences in molecular weight observed in different tissues or species.
• Receptor binding sites: IL-11 interacts with its receptor through specific binding domains. The receptor for IL-11 is a heterodimer composed of the IL-11Rα (Interleukin 11 receptor α chain) and the gp130 (glycoprotein 130), a signal-transducing subunit that is shared by other cytokines in the IL-6 family. IL-11 first binds to IL-11Rα, inducing a conformational change that promotes its interaction with gp130, triggering downstream signaling cascades.

The structural arrangement of IL-11 allows it to activate specific signaling pathways that control various cellular responses, making its structure vital for its role in mediating immune and regenerative functions.

Classification and Subtypes

IL-11 is classified under the IL-6 cytokine family, which is characterized by their signaling through the shared gp130 receptor subunit. Other members of this family include IL-6, IL-27, IL-31, and oncostatin M. These cytokines often overlap in their functions, particularly in inflammatory and immune regulation.

Though IL-11 does not have specific subtypes, it is produced by a wide variety of cells under different conditions:

• Stromal and fibroblast cells: These are the primary producers of IL-11, particularly in tissues undergoing fibrosis or regeneration.
• Epithelial cells: IL-11 is secreted by epithelial cells, especially during inflammatory responses in the gastrointestinal tract and lungs.
• Endothelial cells: In response to injury or hypoxia, endothelial cells may produce IL-11, contributing to vascular repair and inflammation.

The production and activity of IL-11 are context-dependent, and its effects are largely determined by the local tissue environment and the presence of other cytokines or signaling molecules.

Function and Biological Significance

IL-11 is a pleiotropic cytokine with multiple roles in different biological processes, including hematopoiesis, immune regulation, tissue fibrosis, and tumorigenesis.

Primary Functions:

1. Hematopoiesis: IL-11 was originally discovered as a growth factor for hematopoietic cells. It primarily stimulates megakaryocyte maturation and platelet production, making it essential for maintaining normal platelet counts. IL-11’s ability to support hematopoiesis has led to its clinical use in treating chemotherapy-induced thrombocytopenia, a condition characterized by low platelet levels in patients undergoing cancer treatment.
2. Bone Remodeling: IL-11 plays a significant role in regulating bone turnover. It promotes osteoclastogenesis, which is the process of forming bone-resorbing osteoclasts, and contributes to bone remodeling and mineral homeostasis. This makes IL-11 important for maintaining bone integrity, particularly during periods of rapid bone growth or following injury.
3. Fibrosis: One of the most significant recent findings regarding IL-11 is its role in fibrotic diseases. IL-11 is a potent inducer of fibrosis in various tissues, including the heart, lungs, liver, and kidneys. In these tissues, IL-11 promotes the differentiation of fibroblasts into myofibroblasts, cells responsible for the excessive production of extracellular matrix proteins like collagen, leading to tissue scarring and dysfunction. Elevated IL-11 levels have been associated with pulmonary fibrosis, cardiac fibrosis, and liver cirrhosis, highlighting its central role in fibrotic disease progression.
4. Inflammation and Immune Regulation: IL-11 exerts anti-inflammatory effects in some contexts, particularly by modulating the activity of macrophages and reducing pro-inflammatory cytokine production. This contrasts with other members of the IL-6 family, which tend to promote inflammation. IL-11's ability to limit inflammatory damage in tissues has potential therapeutic implications for diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA).
5. Tumorigenesis: In cancer, IL-11 has both pro-tumorigenic and anti-tumorigenic roles, depending on the tissue context. It has been found to promote tumor growth in several cancers, including gastric cancer, colorectal cancer, and breast cancer. IL-11 supports cancer progression by enhancing angiogenesis, cell proliferation, and immune evasion. It also promotes cancer-associated fibroblast activity, which supports tumor growth and metastasis. Given its role in tumorigenesis, IL-11 is an emerging target for cancer therapy.

Clinical Issues

The clinical implications of IL-11 span several disease states, particularly in hematological disorders, fibrotic diseases, and cancer. Dysregulation of IL-11 signaling can lead to pathological conditions, while therapeutic manipulation of IL-11 has been explored for both its beneficial and harmful effects.

Key Clinical Issues:

1. Hematological Disorders: IL-11 has been used clinically as a therapeutic agent for patients with chemotherapy-induced thrombocytopenia. Recombinant human IL-11 (rhIL-11, oprelvekin) is approved for use in increasing platelet counts in cancer patients undergoing chemotherapy. However, side effects such as fluid retention and cardiovascular complications have limited its widespread use.
2. Fibrotic Diseases: Elevated IL-11 levels have been strongly associated with tissue fibrosis. In diseases like idiopathic pulmonary fibrosis (IPF), cardiac fibrosis, and liver fibrosis, IL-11 contributes to excessive extracellular matrix production, leading to tissue scarring and organ dysfunction. Therapeutic strategies aimed at inhibiting IL-11 signaling are under investigation as potential treatments for these fibrotic conditions.
3. Cancer: IL-11 has been implicated in the progression of various cancers, especially in gastrointestinal and breast cancers. By promoting tumor cell survival, angiogenesis, and immune evasion, IL-11 contributes to tumor growth and metastasis. Targeting IL-11 or its signaling pathway is currently being explored as a novel approach to cancer therapy, particularly in cancers where IL-11 plays a prominent role in the tumor microenvironment.
4. Cardiovascular Disease: IL-11 has been linked to cardiac fibrosis and heart failure. Elevated IL-11 levels contribute to the excessive deposition of fibrous tissue in the heart, leading to reduced cardiac function. Inhibiting IL-11 signaling is being studied as a potential therapeutic strategy to prevent or reverse heart fibrosis and improve cardiac outcomes in heart disease patients.

Summary

IL-11 is a multifaceted cytokine with critical roles in hematopoiesis, tissue fibrosis, immune regulation, and cancer progression. Structurally, IL-11 belongs to the IL-6 cytokine family, characterized by a four-α-helix bundle and signaling through the gp130 receptor complex. Initially recognized for its role in supporting platelet production, IL-11 is now known to be involved in many biological processes, including bone remodeling, immune regulation, and tumorigenesis.

Clinically, IL-11 has been utilized in the treatment of thrombocytopenia but is also a key player in fibrotic diseases and cancer. Its dual role in promoting both protective and pathogenic effects makes it a target of interest for various therapeutic interventions, particularly in conditions such as pulmonary fibrosis, cardiac fibrosis