Novel Biphasic Role of LipoxinA4 on Expression of Cyclooxygenase-2 in Lipopolysaccharide-Stimulated Lung Fibroblasts

Abstract

Fibroblasts are important to host defence and immunity, can also as initiators of inflammation as well. As the endogenous “braking signal”, Lipoxins can regulate anti-inflammation and the resolution of inflammation. We investigated the effect of lipoxinA4 on the expression of cyclooxygenase-2 in lipopolysaccharide-stimulated lung fibroblasts. We demonstrated that the expression of cyclooxygenase-2 protein was significantly increased and peaked initially at 6 hours, with a second increase, with maximal levels occurring 24 hours after lipopolysaccharide challenge. ProstaglandinE2 levels also peaked at 6 hours, and prostaglandinD2 levels were increased at both 6 and 24 hours. Exogenous lipoxinA4 inhibited the first peak of cyclooxygenase-2 expression as well as the production of prostaglandinE2 induced by lipopolysaccharide in a dose-dependent manner. In contrast, exogenous lipoxinA4 increased the second peak of cyclooxygenase-2 expression as well as the production of prostaglandinD2 induced by lipopolysaccharide in a dose-dependent manner. LipoxinA4 receptor mRNA expression was markedly stimulated by lipopolysaccharide but inhibited by lipoxinA4. We present evidence for a novel biphasic role of lipoxinA4 on the expression of cyclooxygenase-2 in lipopolysaccharide-stimulated lung fibroblasts, whereby LXA4 has an anti-inflammatory and proresolving activity in lung fibroblasts following LPS stimulation.