Thermal injury alters macrophage responses to prostaglandin E2:: contribution to the enhancement of inducible nitric oxide synthase activity

Prostaglandin E-2 (PGE(2)) and macrophage (M phi) -derived reactive nitrogen intermediates (RNI) have been implicated in T cell dysfunction after thermal injury. Normally, M phi inducible nitric oxide synthase (iNOS) activity can be regulated by PGE(2), however, it is unknown whether PGE(2) modulates M phi iNOS activity after thermal injury. Splenic M phi isolated from mice 7 days after thermal injury produced higher levels of RNI than M phi from sham mice when stimulated with lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in combination. PGE(2), when added concurrently with LPS, suppressed RNI production by M phi from sham mice, whereas M phi from injured mice were unaffected, When M phi were pretreated with PGE(2) before LPS, RNI production was suppressed in both populations. RNI production in response to IFN-gamma or IFN-gamma and TNF-alpha in combination was enhanced by PGE(2) in both populations, however, the effect was markedly greater in M phi from injured mice, The PGE(2)-mediated changes in RNI production were paralleled by similar changes in iNOS protein expression, suggesting that the effect of PGE(2) was at the level of enzyme expression rather than activity, Dibutryl cAMP induced similar effects as PGE(2), suggesting the response to PGE(2) after thermal injury is independent of potential changes in PGE(2)-induced adenylate cyclase activity and is cAMP-mediated, The results indicate that M phi from burned mice display an altered sensitivity to PGE(2), resulting in enhanced iNOS activity. Thus, PGE(2), which is elevated after thermal injury and can directly suppress T cell function, may also contribute to immune dysfunction through the enhancement of M phi iNOS activity.