Modulation of inducible nitric oxide synthase induction by prostaglandin E₂ in macrophages: Distinct susceptibility in murine J774 and RAW 264.7 macrophages

Prostaglandin E₂ (PGE₂) is the major cyclooxygenase metabolite in macrophages with complex proinflammatory and immunoregulatory properties. In the present study, we have compared the modulatory role of PGE₂/cAMP- dependent signaling on induced nitric oxide (NO) production in two murine macrophages, J774 and RAW 264.7. With no effect on NO release by itself, PGE₂ co-addition with lipopolysaccharide (LPS) resulted in a concentration- dependent enhancement in NO release and inducible NO synthase induction in J774, but not in RAW 264.7, macrophages. The potentiation effect of PGE₂ in J774 cells was still seen when applied within 9 h after LPS treatment. Whereas RAW 264.7 macrophages release PGE₂ with greater extent than J774 macrophages in response to LPS, indomethacin and NS-398, upon abolishing LPS- induced PGE₂ release, caused a more obvious inhibition of NO release from J774 than RAW 264.7 cells. Thus, we suggest a higher positive modulatory role of PGE₂ - either endogenous or exogenous - on NO formation in J774 cells. Supporting these findings, exogenous PGE₂ triggers cAMP formation in J774 cells with higher potency and efficacy. Of interest, dBcAMP also elicits higher sensitivity in potentiating NO release in J774 cells. We conclude that the opposite effect of PGE₂/cAMP signaling on macrophage NO induction depends on its signaling efficacy and might be associated with the difference in endogenous PGE₂ levels.