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Interleukin-6 and its receptor: from bench to bedside
Jürgen Scheller1, Stefan Rose-John
1Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstr 40, 24098 Kiel, Germany.
Insights
Interleukin-6 (IL-6) signaling occurs through membrane-bound receptors and a novel pathway called trans-signaling, utilizing soluble IL-6 receptors. This discovery enables the development of designer cytokines for therapeutic applications in various diseases.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Interleukin-6 (IL-6) is a key inflammatory cytokine implicated in cancer and inflammation.
- IL-6 signaling typically involves binding to membrane-bound IL-6 receptors (IL-6R) and the gp130 co-receptor.
- Some cells lack membrane-bound IL-6R and are unresponsive to IL-6 via classical signaling.
Purpose of the Study:
- To review the mechanisms of IL-6 signaling, including classical signaling and trans-signaling.
- To highlight the role of soluble IL-6 receptor (sIL-6R) in enabling IL-6 to signal through gp130 on IL-6R-deficient cells.
- To introduce designer cytokines engineered to modulate IL-6 trans-signaling.
Main Methods:
- Review of existing literature on IL-6 signaling pathways.
- Analysis of data demonstrating the function of soluble IL-6R in trans-signaling.
- Description of the development and application of designer cytokines.
Main Results:
- IL-6 utilizes both classical signaling and trans-signaling pathways in physiological and pathophysiological contexts.
- Soluble IL-6R forms a complex with IL-6, enabling signaling in cells lacking membrane-bound IL-6R.
- Designer cytokines can specifically enhance or inhibit IL-6 trans-signaling.
Conclusions:
- IL-6 trans-signaling is a critical mechanism in various biological processes.
- Designer cytokines offer a targeted approach for therapeutic interventions.
- Targeting IL-6 trans-signaling holds promise for treating conditions like chronic inflammation, cancer, and for regenerative medicine applications.
Abstract:
Interleukin-6 (IL-6) is an inflammatory cytokine with a well-documented role in inflammation and cancer. The cytokine binds to a membrane bound IL-6 receptor (IL-6R) and this complex associates with two molecules of the signal transducing protein gp130 thereby initiating intracellular signaling. While gp130 is present on most if not all cells of the body, the IL-6R is only present on some cells, mainly hepatocytes and several leukocytes. Cells, which only express gp130 and no IL-6R are refractory to IL-6 signals. We have shown earlier that the IL-6R can exist as a soluble protein generated by limited proteolysis of the membrane bound receptor or by translation from an alternatively spliced mRNA. This soluble IL-6R (sIL-6R) can bind the ligand IL-6 and the soluble complex of sIL-6R and IL-6 can bind to gp130 on cells which lack the membrane bound IL-6R and trigger gp130 signaling. We have named this process 'trans-signaling'. We will review data, which clearly show that IL-6 uses classical signaling via the membrane bound receptor and trans-signaling via the soluble receptor in various physiological and pathophysiological situations. Furthermore, we have developed designer cytokines, which can specifically enhance or inhibit IL-6 trans-signaling. These designer cytokines have been shown to be extremely useful to in therapeutic applications ranging from the long-term culture of stem cells and enhancing liver regeneration up to the blockade of chronic inflammation and cancer.
