Oncostatin M: Development of a pleiotropic cytokine

Oncostatin M (OM) is a member of the interleukin-6 (IL-6) cytokine subfamil y. 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 e xpression and alters the production of proteases that down-regulate inflamm ation. Administration of OM to lipopolysaccharide (LPS)-challenged mice low ered serum tumor necrosis factor-alpha (TNF-alpha) levels and decreased the lethal effects of LPS administration. OM also reduced inflammation in anim al models of human disease, including inflammatory bowel disease, antibody- induced arthritis, and experimental autoimmune encephalomyelitis. Preclinic al safety studies have been conducted in the mouse and monkey. Mice were ad ministered OM (subcutaneously) at 72, 360, or 1,560 mu g/kg/day in a 2-wk t oxicity study. Decreased body weights occurred at 1,560 mu g/kg. Drug-relat ed changes at 360 and 1,560 mu g/kg consisted of dermal irritation at the i njection site, leukopenia, and thymic lymphoid depletion; all changes were reversible following a 2-wk recovery period. In a 2-wk subcutaneous study i n monkeys, OM was administered at 1, 5, 15, 45, or 150 mu g/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 mu g/kg cons isted of reversible elevations in both serum amyloid A and IL-6, and revers ible thymic lymphoid depletion. Transient increases in body temperature occ urred at 15, 45, and 150 mu g/kg. The observed spectrum of immunomodulatory effects suggests that OM may have therapeutic utility in treating chronic inflammatory diseases.