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Interleukin-6: from basic biology to selective blockade of pro-inflammatory activities
Jürgen Scheller1, Christoph Garbers2, Stefan Rose-John2
1Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
Seminars in Immunology
|December 12, 2013
Summary
Interleukin-6 (IL-6) trans-signaling, mediated by soluble IL-6 receptors, drives inflammatory diseases and cancer. Blocking this pathway with sgp130Fc shows therapeutic potential in preclinical models.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Cytokine receptors, including interleukin-6 receptor (IL-6R), exist in membrane-bound and soluble forms.
- Soluble IL-6R, generated via proteolysis or splicing, forms complexes with IL-6.
- This IL-6/soluble IL-6R complex activates cells lacking membrane-bound IL-6R, a process termed trans-signaling.
Purpose of the Study:
- To investigate the role of IL-6 trans-signaling in disease pathogenesis.
- To evaluate sgp130Fc, a selective inhibitor of IL-6 trans-signaling, as a therapeutic agent.
Main Methods:
- Utilized recombinant soluble gp130Fc protein and sgp130Fc transgenic mice.
- Tested sgp130Fc in animal models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis, pancreatitis, colon cancer, ovarian cancer, and pancreatic cancer.
Main Results:
- IL-6 trans-signaling via soluble IL-6R was identified as a critical factor in disease development and progression across multiple models.
- sgp130Fc demonstrated efficacy in blocking IL-6 trans-signaling and mitigating disease.
Conclusions:
- IL-6 trans-signaling is a key therapeutic target for chronic inflammatory diseases and cancer.
- sgp130Fc represents a promising novel therapeutic agent, currently undergoing Phase I clinical trials.
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