UP-REGULATION OF INDUCIBLE CYCLOOXYGENASE GENE-EXPRESSION BY PLATELET-ACTIVATING-FACTOR IN ACTIVATED RAT ALVEOLAR MACROPHAGES

Platelet-activating factor (PAF) can stimulate alveolar macrophages (A M) 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 pro ducts 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 i ncrease in levels of COX-2 mRNA. No significant change was observed in the mRNA expression of the constitutive isoform, COX-1. The antagonis t 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 produc tion of PGE(2). Two relatively selective inhibitors of COX-2 abolished the PAF-dependent increase in PGE(2) production. Moreover, inhibition of transcription with actinomycin D completely abrogated the effect o f PAF on both COX-2 mRNA and PGE(2) 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 interrelatio nship between PAF and prostanoids in the context of allergic, inflamma tory, and immune processes.