INHIBITION BY INTERLEUKIN-10 OF INDUCIBLE CYCLOOXYGENASE EXPRESSION IN LIPOPOLYSACCHARIDE-STIMULATED MONOCYTES - ITS UNDERLYING MECHANISM IN COMPARISON WITH INTERLEUKIN-4

Both interteukin-10 (IL-10) and IL-4 inhibited the prostanoid synthesi s of lipopolysaccharide (LPS)-stimulated human monocytes, and their in hibition was shown to be based on a common mechanism to suppress the g ene expression of inducible cyclooxygenase (COX). COX has been shown t o exist in at least two distinct isoforms, designated COX-1 and COX-2, and their gene expressions exhibit different profiles. At both the pr otein and mRNA levels, the expression of COX-1 was constitutive and wa s not modulated by treatments with LPS. IL-10, or IL-4. In contrast, t he expression of COX-2 was observed only after stimulation with LPS, I L-10 and IL-4 significantly inhibited LPS-induced COX-2 expression. Ki netic studies showed that they inhibited COX-2 mRNA expression within 1 hour after stimulation and that maximal inhibition was consistently observed at 5 hours. Moreover, the addition of cycloheximide (CHX) to LPS-stimulated monocytes resulted in a superinduction of COX-2 mRNA, w hereas CHX almost abrogated the abilities of IL-10 and IL-4 to inhibit this gene expression. Experiments with actinomycin D showed that both cytokines accelerated the degradation of COX-2 mRNA. Furthermore, nuc lear run-on experiments showed that both cytokines modestly inhibited LPS-induced COX-2 gene transcription. Thus, both cytokines seemed to r egulate the COX-related pathway in a similar manner, although their re ceptor systems did not show any structural similarities. Considering r ecent findings showing that the drugs that exhibit a selective effect on COX-2 may be more preferable in inflammatory conditions, such biolo gic activities of IL-10 and IL-4 described above may offer useful tool s in controlling inflammatory disorders in the future. (C) 1995 by The American Society of Hematology.