IL-10 is a central regulator of cyclooxygenase-2 expression and prostaglandin production

IL-IO is a potent anti-inflammatory and immune regulatory cytokine, IL-10(- /-) mice produce exaggerated amounts of inflammatory cytokines when stimula ted with LPS, indicating that endogenous IL-10 is a central regulator of in flammatory cytokine production in vivo. PGs are lipid mediators that are al so produced in large amounts during the inflammatory response. To study the role of IL-10 in the regulation of PG production during the acute inflamma tory response, we evaluated LPS-induced cyclooxygenase (COX) expression and PC production in wild-type (wt) and IL-10(-/-) mice. LPS induced PGE, prod uction from IL-10(-/-) spleen cells was 5.6-fold greater than that from wt spleen cells. LPS stimulation resulted in the induction of COX-2 mRNA and p rotein in both wt and IL-10(-/-) spleen cells; however, the magnitude of in crease in COX-2 mRNA was 5.5-fold greater in IL-10(-/-) mice as compared wi th wt mice. COX-I protein levels mere not affected by LPS stimulation in ei ther wt or IL-10-/mice. Neutralization of IFN-gamma, TNF-alpha or IL-12 mar kedly decreased the induction of COX-2 in IL-10(-/-) spleen cells, suggesti ng that increased inflammatory cytokine production mediates much of the COX -2 induction in IL-10(-/-) mice. Treatment of IL-10(-/-) mice with low dose s of LPS resulted in a marked induction of COX-2 mRNA in the spleen, wherea s wt mice had minimal expression of COX-2 mRNA, These findings indicate tha t, in addition to IL-10's central role in the regulation of inflammatory cy tokines, endogenous IL-10 is an important regulator of PG production in the response to LPS,