IL6ST - interleukin 6 cytokine family signal transducer Elisa - Clia - Antibody - Protein

Background

The interleukin 6 signal transducer (IL6ST), also known as gp130 or CD130, is a transmembrane protein that plays a crucial role in immune system regulation and cellular signaling. It functions as a common signal transducer for the IL-6 family of cytokines, which includes IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and others. These cytokines are involved in various physiological processes, including immune responses, hematopoiesis, inflammation, and tissue regeneration.

IL6ST/gp130 is a key receptor component in the JAK/STAT signaling pathway and is widely expressed in various cell types, including immune cells, neurons, hepatocytes, and endothelial cells. Its broad expression and signaling capability allow it to mediate responses across different tissues, contributing to a range of cellular functions such as proliferation, differentiation, survival, and apoptosis. Dysregulation of gp130 signaling has been associated with multiple conditions, including autoimmune diseases, chronic inflammatory disorders, and various cancers.

Protein Structure

The IL6ST/gp130 protein is a type I transmembrane protein that consists of 918 amino acids in humans and has a molecular weight of around 130 kDa. Its structure can be divided into three main regions: the extracellular domain (ECD), the transmembrane domain (TMD), and the intracellular domain (ICD), each contributing to its functional versatility in signal transduction.

Extracellular Domain (ECD):

• The ECD of gp130 spans approximately 600 amino acids and is composed of six distinct subdomains, which include two cytokine receptor homology regions (CHR1 and CHR2), three fibronectin type III-like (FNIII) domains, and two Ig-like C2-type domains.
• The cytokine-binding regions (CHR1 and CHR2) are necessary for ligand binding and complex formation with other receptors, such as IL-6R (the specific receptor for IL-6). These domains are critical for initiating signaling by enabling the heterodimerization of gp130 with other receptor subunits upon cytokine binding.
• The WSXWS motif is essential within these binding domains, contributing to receptor folding, stability, and cytokine interaction.
• Several N-linked glycosylation sites are present in the ECD, aiding in receptor stability and functional efficiency by increasing the protein’s half-life on the cell surface.

Transmembrane Domain (TMD):

• The TMD of gp130 anchors the receptor within the cell membrane, providing structural integrity and positioning for optimal interaction with extracellular ligands and intracellular signaling molecules. This domain consists of a single hydrophobic α-helix.

Intracellular Domain (ICD):

• The ICD of gp130, about 277 amino acids long, contains several conserved tyrosine residues that serve as docking sites for signaling molecules. Upon cytokine binding, these tyrosine residues become phosphorylated, initiating downstream signaling cascades.
• The intracellular domain interacts with members of the Janus kinase (JAK) family, primarily JAK1 and JAK2, which phosphorylate STAT (Signal Transducer and Activator of Transcription) proteins upon receptor activation. In addition to the JAK/STAT pathway, IL6ST signaling also activates the MAPK/ERK and PI3K/AKT pathways, diversifying its downstream effects.

Classification and Subtypes

IL6ST is classified as a type I cytokine receptor and belongs to the hematopoietin receptor superfamily. Within this superfamily, IL6ST is grouped under the IL-6 cytokine family receptors due to its shared usage as a signaling subunit by multiple IL-6 family cytokines. IL6ST itself does not have subtypes, but it interacts with various specific cytokine receptors, including IL-6R, IL-11R, LIF receptor, and others. These interactions confer functional diversity, allowing IL6ST to mediate distinct cellular responses depending on the cytokine and receptor complex involved.

Function and Biological Significance

IL6ST functions as a signal transducer for several cytokines in the IL-6 family, mediating a wide array of biological effects:

Immune and Inflammatory Responses:

• IL6ST plays a crucial role in immune cell activation and differentiation. By mediating IL-6 signaling, it regulates T and B cell proliferation, antibody production, and differentiation of T helper cells, especially Th17 cells, which are involved in autoimmune and inflammatory responses.
• The gp130/IL-6R complex is essential in activating acute-phase responses, which mobilize immune cells to infection sites, induce fever, and stimulate the production of C-reactive protein in the liver.

Cell Proliferation and Survival:

• Through its downstream activation of STAT3, gp130 signaling promotes cell proliferation, survival, and anti-apoptotic responses. These properties are particularly relevant in hepatocytes, where IL-6/gp130 signaling supports liver regeneration after injury.
• In neural tissues, IL6ST supports the survival and differentiation of neurons, especially under stress conditions. This neurotrophic effect has implications in both neurodevelopment and neurodegenerative diseases.

Hematopoiesis and Bone Remodeling:

• IL6ST signaling is involved in the differentiation and maturation of hematopoietic cells, influencing the production of red and white blood cells. It plays a role in erythropoiesis, thrombopoiesis, and granulocyte formation.
• It also contributes to bone homeostasis by influencing osteoclast differentiation and activity, often in conjunction with IL-11.

Cell Growth and Oncogenesis:

• Aberrant activation of gp130, especially via the STAT3 pathway, has been implicated in various cancers, including multiple myeloma, colorectal cancer, and glioma. STAT3 activation leads to uncontrolled cell growth and inhibition of apoptosis, both hallmark features of cancer.
• In certain cancers, mutations in gp130 or excessive production of IL-6 result in persistent STAT3 activation, contributing to tumor growth, angiogenesis, and immune evasion. This makes gp130 a potential target in cancer therapies aiming to inhibit IL-6 family cytokine signaling.

Clinical Issues

Abnormal IL6ST signaling is implicated in numerous clinical conditions:

Autoimmune and Inflammatory Diseases:

• Overactive IL6ST signaling, often via excessive IL-6 production, is a central factor in chronic inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). High IL-6 levels contribute to inflammation, autoantibody production, and tissue damage in these conditions.
• In rheumatoid arthritis, for instance, IL6ST signaling enhances the differentiation of Th17 cells, which produce IL-17 and further drive joint inflammation. IL-6 inhibitors, such as tocilizumab, target IL-6R to modulate this pathway, reducing inflammation and disease symptoms.

Cancers:

• Dysregulated IL6ST/STAT3 signaling is frequently associated with malignancies. In particular, gp130 mutations or chronic IL-6 stimulation contribute to persistent STAT3 activation, promoting tumor growth, metastasis, and resistance to apoptosis. Targeting gp130 or STAT3 in cancer cells has become an area of research for therapeutic intervention.
• In multiple myeloma, for example, IL-6-driven gp130 signaling is a critical factor in disease progression, making gp130 a promising target for inhibiting tumor growth.

Cardiovascular and Metabolic Disorders:

• Elevated IL6ST signaling has been associated with metabolic syndromes, insulin resistance, and cardiovascular diseases. In metabolic syndromes, IL-6 produced by adipose tissue can activate gp130 pathways, leading to chronic low-grade inflammation and contributing to insulin resistance.
• Cardiovascular diseases may also involve IL6ST signaling, as IL-6 and IL-11 influence inflammation and fibrosis within cardiac tissue.

Neurological Disorders:

• IL6ST has neuroprotective functions and is involved in neurogenesis, but dysregulated signaling can contribute to neuroinflammation and neurodegenerative diseases. Elevated IL-6 levels and subsequent gp130 signaling have been observed in conditions such as Alzheimer’s disease, suggesting a role for IL6ST in modulating brain inflammation and neurodegeneration.

Summary

IL6ST, or gp130, is a versatile and essential transmembrane protein that functions as a common signal transducer for cytokines in the IL-6 family, influencing immunity, inflammation, cell proliferation, and survival. Structurally, IL6ST consists of an extracellular cytokine-binding domain, a transmembrane domain, and an intracellular domain, which together mediate downstream JAK/STAT, MAPK, and PI3K/AKT signaling. This receptor's ability to partner with different cytokine receptors makes it central to a wide range of physiological and pathological processes.

Clinically, aberrant gp130 signaling is linked to autoimmune diseases, cancers, metabolic disorders, and neurodegeneration, making it a valuable therapeutic target. Therapies that modulate IL6ST signaling pathways, such as IL-6 blockers in rheumatoid arthritis, provide effective treatments for diseases where excessive inflammation and immune activation are central factors. Ongoing research continues to explore the therapeutic potential of targeting IL6ST and its downstream pathways in diseases characterized by chronic inflammation and oncogenesis.