Up-regulation of inducible cyclooxygenase gene expression by platelet-activating factor in activated rat alveolar macrophages.

Abstract

Platelet-activating factor (PAF) can stimulate alveolar macrophages (AM) to produce IL-6 through a PG-dependent process. In this study, the modulation by PAF of the expression of COX-2, the inducible isoform of PG synthase, was investigated. Expression of COX-2 mRNA was increased in rat AM within 2 h after treatment with either of the bacterial products LPS or muramyl dipeptide (MDP) alone. Although PAF had no effect by itself, stimulation of AM with a combination of PAF (10(-10) to 10(-8) M) and LPS or MDP resulted in a synergistic, three- to fivefold increase in levels of COX-2 mRNA. No significant change was observed in the mRNA expression of the constitutive isoform, COX-1. The antagonist WEB 2170 blocked the action of PAF, whereas lyso-PAF was inactive on the COX-2 gene expression. The effect of PAF was rapid, being evident by 30 to 60 min of stimulation and was accompanied by enhanced production of PGE2. Two relatively selective inhibitors of COX-2 abolished the PAF-dependent increase in PGE2 production. Moreover, inhibition of transcription with actinomycin D completely abrogated the effect of PAF on both COX-2 mRNA and PGE2 production. These results suggest that COX-2 expression can be regulated at the transcriptional level by PAF, in synergy with bacterial products. PAF-dependent up-regulation of COX-2 expression may constitute a novel element in the interrelationship between PAF and prostanoids in the context of allergic, inflammatory, and immune processes.