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Published on: September 13, 2017
Oncostatin M: development of a pleiotropic cytokine
J K Loy1, T J Davidson, K K Berry
1Department of Experimental Pathology, Bristol-Myers Squibb, Princeton, New Jersey 08543, USA. loyj@bms.com
Abstract:
Oncostatin M (OM) is a member of the interleukin-6 (IL-6) cytokine subfamily. The binding of OM to its receptor initiates signal transduction through JAK-signal transducers and activators of transcription (STAT) pathways and activates transcription activators through mitogen-activated protein (MAP) kinases. Results of in vitro assays documented that OM modulates cytokine expression and alters the production of proteases that down-regulate inflammation. Administration of OM to lipopolysaccharide (LPS)-challenged mice lowered serum tumor necrosis factor-alpha (TNF-alpha) levels and decreased the lethal effects of LPS administration. OM also reduced inflammation in animal models of human disease, including inflammatory bowel disease, antibody-induced arthritis, and experimental autoimmune encephalomyelitis. Preclinical safety studies have been conducted in the mouse and monkey. Mice were administered OM (subcutaneously) at 72, 360, or 1,560 micrograms/kg/day in a 2-wk toxicity study. Decreased body weights occurred at 1,560 micrograms/kg. Drug-related changes at 360 and 1,560 micrograms/kg consisted of dermal irritation at the injection site, leukopenia, and thymic lymphoid depletion; all changes were reversible following a 2-wk recovery period. In a 2-wk subcutaneous study in monkeys, OM was administered at 1, 5, 15, 45, or 150 micrograms/kg/day. At all doses there was reversible, transient inappetence and dermal irritation at the injection site. Drug-related changes at 5, 15, 45, and 150 micrograms/kg consisted of reversible elevations in both serum amyloid A and IL-6, and reversible thymic lymphoid depletion. Transient increases in body temperature occurred at 15, 45, and 150 micrograms/kg. The observed spectrum of immunomodulatory effects suggests that OM may have therapeutic utility in treating chronic inflammatory diseases.
Insights
Oncostatin M (OM), an IL-6 cytokine, reduces inflammation and lethal effects in animal models. Preclinical studies show reversible side effects, suggesting therapeutic potential for chronic inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Oncostatin M (OM) is a cytokine within the interleukin-6 (IL-6) subfamily, mediating biological effects through JAK-STAT and MAP kinase pathways.
- OM influences cytokine expression and protease production, impacting inflammatory responses.
- OM exhibits anti-inflammatory properties, reducing tumor necrosis factor-alpha (TNF-alpha) and mitigating lethal effects of lipopolysaccharide (LPS) in mice.
Framework:
- OM's mechanism involves binding to its receptor, initiating intracellular signaling cascades.
- In vitro studies demonstrate OM's capacity to modulate cytokine profiles and protease activity.
- In vivo studies utilized LPS-challenged mice and animal models of inflammatory diseases to assess OM's efficacy.
Implementation:
- OM administration in LPS-challenged mice led to reduced serum TNF-alpha levels and improved survival rates.
- Therapeutic efficacy was observed in animal models for inflammatory bowel disease, arthritis, and experimental autoimmune encephalomyelitis.
- Preclinical safety evaluations involved subcutaneous administration in mice and monkeys at various dose levels.
Implications:
- Observed immunomodulatory effects suggest OM's potential as a therapeutic agent for chronic inflammatory conditions.
- Reversible adverse effects noted in preclinical safety studies, including dermal irritation and transient changes in blood parameters, inform dosage and administration strategies.
- Further research into OM's therapeutic applications is warranted based on its demonstrated anti-inflammatory and immunomodulatory capabilities.
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