IL-1 alpha and TNF alpha down-regulate CRH receptor-2 mRNA expression in the mouse heart

Two receptors (CRH receptor type 1 and CRH receptor type 2) have been ident ified for the stress-induced neuropeptide, CRH and related peptides, urocor tin, and urocortin II. We previously found marked down-regulation of cardia c CRH receptor type 2 expression following administration of bacterial endo toxin, lipopolysaccharide, a model of systemic immune activation, and infla mmation. We postulated that inflammatory cytokines may regulate CRH recepto r type 2. We show that systemic IL-1 alpha administration significantly dow n-regulates CRH receptor type 2 mRNA in mouse heart. In addition, TNF alpha treatment also reduces CRH receptor type 2 mRNA expression, although the e ffect was not as marked as with IL-1a. However, CRH receptor type 2 mRNA ex pression is not altered in adult mouse ventricular cardiomyocytes stimulate d in vitro with TNF alpha or IL-1 alpha. Thus, cytokine regulation may be i ndirect. Exogenous administration of corticosterone in vivo or acute restra int stress also reduces cardiac CRH receptor type 2 mRNA expression, but li ke cytokines, in vitro corticosterone treatment does not modulate expressio n in cardiomyocytes. Interestingly, treatment with urocortin significantly decreases CRH receptor type 2 mRNA in cultured cardiomyocytes. We speculate that in vivo, inflammatory mediators such as lipopolysaccharide and/or cyt okines may increase urocortin, which in turn down-regulates CRH receptor ty pe 2 expression in the heart. Because CRH and urocortin increase cardiac co ntractility and coronary blood flow, impaired CRH receptor type 2 function during systemic inflammation may ultimately diminish the adaptive cardiac r esponse to adverse conditions.