Two receptors (CRH receptor type 1 and CRH receptor type 2) have been identified for the stress-induced neuropeptide, CRH and related peptides, urocortin, and urocortin II. We previously found marked down-regulation of cardiac CRH receptor type 2 expression following administration of bacterial endotoxin, lipopolysaccharide, a model of systemic immune activation, and inflammation. We postulated that inflammatory cytokines may regulate CRH receptor type 2. We show that systemic IL-1α administration significantly down-regulates CRH receptor type 2 mRNA in mouse heart. In addition, TNFα treatment also reduces CRH receptor type 2 mRNA expression, although the effect was not as marked as with IL-1α. However, CRH receptor type 2 mRNA expression is not altered in adult mouse ventricular cardiomyocytes stimulated in vitro with TNFα or IL-1α. Thus, cytokine regulation may be indirect. Exogenous administration of corticosterone in vivo or acute restraint stress also reduces cardiac CRH receptor type 2 mRNA expression, but like cytokines, in vitro corticosterone treatment does not modulate expression 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 cytokines may increase urocortin, which in turn down-regulates CRH receptor type 2 expression in the heart. Because CRH and urocortin increase cardiac contractility and coronary blood flow, impaired CRH receptor type 2 function during systemic inflammation may ultimately diminish the adaptive cardiac response to adverse conditions.
Sarah C. Coste, Kurt A. Heldwein, Susan L. Stevens, Eric Tobar-Dupres, Mary P. Stenzel-Poore
IL-1α and TNF-α down-regulate CRH receptor-2 mRNA expression in the mouse heart.
Endocrinology, 2001, volume 142, issue 8, pages 3537-3545
Coste, Sarah C.; Heldwein, Kurt A.; Stevens, Susan L.; Tobar-Dupres, Eric; and Stenzel-Poore, Mary P., "IL-1α and TNF-α Down-Regulate CRH Receptor-2 mRNA Expression in the Mouse Heart" (2001). Faculty Publications. Published Version. Submission 7.