IL6R

Official Full Name

interleukin 6 receptor

Organism

Homo sapiens

GeneID

3570

Background

This gene encodes a subunit of the interleukin 6 (IL6) receptor complex. Interleukin 6 is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in the immune response. The IL6 receptor is a protein complex consisting of this protein and interleukin 6 signal transducer (IL6ST/GP130/IL6-beta), a receptor subunit also shared by many other cytokines. Dysregulated production of IL6 and this receptor are implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. Alternatively spliced transcript variants encoding distinct isoforms have been identified in this gene. A pseudogene of this gene is found on chromosome 9. [provided by RefSeq, Aug 2020]

Synonyms

IL6Q; gp80; CD126; HIES5; IL-6R; IL6RA; IL6RQ; IL-1Ra; IL-6RA; IL6QTL; IL-6R-1;

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Detailed Information

The IL-6R gene encodes the α subunit of the interleukin-6 receptor complex. This protein is a type I transmembrane glycoprotein whose extracellular region comprises an immunoglobulin-like domain and two fibronectin type III domains, mediating low-affinity, specific binding to its ligand IL-6. However, the IL-6Rα subunit itself lacks intrinsic signaling capability and requires association with another transmembrane protein, gp130 (the IL-6 signal transducer shared by all gp130-utilizing cytokines), to initiate downstream signal transduction. A key feature of IL-6R is its existence in two major forms: membrane-bound IL-6R (mIL-6R) and soluble IL-6R (sIL-6R). sIL-6R is primarily generated by proteolytic cleavage of the membrane-bound receptor and can also arise via alternative splicing. This soluble receptor is not merely an antagonist; rather, it can form a complex with IL-6 and activate gp130-expressing cells, a process known as "trans-signaling," which greatly expands the cellular response spectrum of IL-6.

Biological Significance

IL-6R serves as the gateway mediating the pleiotropic biological effects of IL-6. Through three distinct signaling modes-classical signaling, trans-signaling, and cluster signaling-it precisely regulates IL-6's functional output under physiological and pathological conditions. Classical signaling occurs in a limited set of cells expressing mIL-6R, such as hepatocytes and certain leukocyte subsets. IL-6 binding to mIL-6R recruits and homodimerizes gp130, primarily activating the JAK/STAT3 pathway, while also engaging MAPK and PI3K pathways, mediating regenerative, anti-inflammatory, and some pro-inflammatory effects, including the synthesis of acute-phase proteins in the liver and lymphocyte differentiation. In contrast, trans-signaling is the main driver of IL-6's pro-inflammatory effects. IL-6/sIL-6R complexes can engage any gp130-expressing cell, bypassing the restriction of mIL-6R expression and allowing previously unresponsive cells, such as endothelial cells, smooth muscle cells, and various epithelial cells, to respond to IL-6. This mechanism plays a central role in chronic inflammation, autoimmune disorders, and tumor progression.

Cluster signaling represents a third mode, wherein mIL-6R-expressing cells present IL-6 to gp130 on adjacent cells, enabling intercellular communication that may modulate the local immune microenvironment. The diversity of IL-6R forms and signaling modes collectively dictates IL-6's complex actions in host defense, tissue repair, hematopoietic support, metabolic regulation, and pathologic conditions such as chronic inflammation and cancer.

Figure 1. Production sources and main signaling pathways of IL-6. (Xu J, et al., 2021)

Clinical Relevance

IL-6R's clinical significance is highlighted by its role as a key therapeutic target, particularly in autoimmune and chronic inflammatory diseases. Since IL-6 trans-signaling mediates the pathological pro-inflammatory effects of IL-6, direct targeting of IL-6R provides an effective strategy to block this pathway. Tocilizumab, a humanized monoclonal antibody against IL-6R, blocks both classical and trans-signaling and has been approved for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, and cytokine release syndrome, demonstrating the central role of the IL-6/IL-6R axis in these diseases. In addition, circulating sIL-6R levels are considered potential biomarkers for disease activity in various inflammatory conditions.

Therapeutic targeting of IL-6R also faces challenges. IL-6 is essential for host defense (e.g., antibacterial responses) and metabolic homeostasis (e.g., lipid metabolism), so complete blockade can result in neutropenia, elevated liver enzymes, dyslipidemia, and increased risk of certain infections. Future research aims to develop more precise interventions, such as therapies that selectively inhibit trans-signaling while preserving protective classical signaling, or to identify patient populations most likely to benefit from anti-IL-6R treatment through biomarker stratification. In oncology, IL-6 trans-signaling is implicated in tumor cell proliferation, survival, angiogenesis, metastasis, and tumor-associated cachexia, and anti-IL-6R therapies are under clinical investigation in multiple malignancies. Continued study of IL-6R biology, particularly the context-specific roles of its signaling modes, will facilitate the development of safer and more effective targeted therapies.

References

Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012;8(9):1237–1247.
Scheller J, Chalaris A, Schmidt-Arras D, et al. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–888.
Tanaka T, Narazaki M, Kishimoto T. Interleukin (IL-6) Immunotherapy. Cold Spring Harb Perspect Biol. 2018;10(8):a028456.
Xu J, Lin H, Wu G, et al. IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma. Front Oncol. 2021 Dec 15;11:760971.

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