Oncostatin M: development of a pleiotropic cytokine.
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.
Loy
J K
JK
Department of Experimental Pathology, Bristol-Myers Squibb, Princeton, New Jersey 08543, USA. loyj@bms.com
Davidson
T J
TJ
Berry
K K
KK
Macmaster
J F
JF
Danle
B
B
Durham
S K
SK
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D016207:Cytokines; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D053683:Oncostatin M