Thermal injury alters macrophage responses to prostaglandin E-2: contribution to the enhancement of inducible nitric oxide synthase activity

Prostaglandin E-2 (PGE(2)) and macrophage (M phi) -derived reactive nitroge n intermediates (RNI) have been implicated in T cell dysfunction after ther mal injury. Normally, M phi inducible nitric oxide synthase (iNOS) activity can be regulated by PGE(2), however, it is unknown whether PGE(2) modulate s M phi iNOS activity after thermal injury. Splenic M phi isolated from mic e 7 days after thermal injury produced higher levels of RNI than M phi from sham mice when stimulated with lipopolysaccharide (LPS) or interferon-gamm a (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in combination. P GE(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 ph i 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, howeve r, the effect was markedly greater in M phi from injured mice, The PGE(2)-m ediated changes in RNI production were paralleled by similar changes in iNO S protein expression, suggesting that the effect of PGE(2) was at the level of enzyme expression rather than activity, Dibutryl cAMP induced similar e ffects as PGE(2), suggesting the response to PGE(2) after thermal injury is independent of potential changes in PGE(2)-induced adenylate cyclase activ ity and is cAMP-mediated, The results indicate that M phi from burned mice display an altered sensitivity to PGE(2), resulting in enhanced iNOS activi ty. Thus, PGE(2), which is elevated after thermal injury and can directly s uppress T cell function, may also contribute to immune dysfunction through the enhancement of M phi iNOS activity.