Heme and acute inflammation - Role in vivo of heme in the hepatic expression of positive acute-phase reactants in rats

Acute-phase protein synthesis in the liver during inflammation is regulated via cytokines and glucocorticoids. Using quantitative reverse transcriptio n (RT)-PCR analysis and immunoassay, we explored, in the rat, the response of the acute-phase protein, alpha-2 macroglobulin (A2M), after systemic inf lammation induced by lipopolysaccharide (LPS) or localized inflammation ind uced by turpentine oil (TO). The results indicate that synthesis of A2M is higher following TO-induced inflammation than LPS-induced inflammation and is not correlated with interleukin (IL)-6 or glucocorticoid levels. We stud ied the putative role of heme in this differential A2M expression following localized vs. systemic inflammation; addition of heme during LPS-induced i nflammation can boost the expression of A2M, whereas blocking heme synthesi s (by succinyl acetone) or enhancing its consumption in parallel biosynthet ic pathways (cytochrome P450 induction by phenobarbital) decreases A2M expr ession. This decrease was abolished by exogenous heme supplementation. Fina lly, we demonstrate that heme supplementation is also able to increase the A2M response in female rats to a level similar to that in male rats providi ng a new insight into the puzzling sexual dimorphism observed previously du ring localized inflammation. We propose that heme should be considered a ne w regulatory element in controlling liver A2M expression during inflammatio n.