ONCOSTATIN-M IS A PROINFLAMMATORY MEDIATOR - IN-VIVO EFFECTS CORRELATE WITH ENDOTHELIAL-CELL EXPRESSION OF INFLAMMATORY CYTOKINES AND ADHESION MOLECULES

Oncostatin M is a member of the IL-6 family of cytokines that is prima rily known for its effects on cell growth. Endothelial cells have an a bundance of receptors for oncostatin hi, and may be its primary target . We determined if oncostatin M induces a key endothelial cell functio n, initiation of the inflammatory response, We found that subcutaneous injection of oncostatin RI in mice caused an acute inflammatory react ion, Oncostatin M in vitro stimulated: (a) polymorphonuclear leukocyte (PMN) transmigration through confluent monolayers of primary human en dothelial cells; (b) biphasic PMN adhesion through rapid P-selectin ex pression, and delayed adhesion mediated by E-selectin synthesis; (c) i ntercellular adhesion molecule-1 and vascular cell adhesion molecule-1 accumulation: and (d) the expression of PMN activators IL-6, epitheli al neutrophil activating peptide-78, growth-related cytokine alpha and growth-related cytokine beta without concomitant IL-g synthesis, The nature of the response to oncostatin M varied with concentration, sugg esting high and low affinity oncostatin M receptors independently stim ulated specific responses, Immunohistochemistry showed that macrophage -like cells infiltrating human aortic aneurysms expressed oncostatin R I, so it is present during a chronic inflammatory reaction, Therefore, oncostatin M, but not other IL-6 family members, fulfills Koch's post ulates as an inflammatory mediator, Since its effects on endothelial c ells differ significantly from established mediators like TNF alpha. i t ma uniquely contribute to the inflammatory cycle.