IL-1α and TNFα Down-Regulate CRH Receptor-2 mRNA Expression in the Mouse Heart

• DOI: 10.1210/endo.142.8.8342
• Publication Date: 2014-01-08T16:11:47Z
• Authors: Sarah C. Coste; Kurt A. Heldwein; Susan L. Stevens; Eric Tobar-Dupres; Mary P. Stenzel-P...
• Keywords: Male; Restraint, Physical; 0301 basic medicine; Corticotropin-Releasing Hormone; Interleukin-6; Tumor Necrosis Factor-alpha; Heart Ventricles; Myocardium; Down-Regulation; Cell Separation; Receptors, Corticotropin-Releasing Hormone; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Animals; Protein Isoforms; Female; RNA, Messenger; Corticosterone; Urocortins; Interleukin-1

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-1alpha administration significantly down-regulates CRH receptor type 2 mRNA in mouse heart. In addition, TNFalpha treatment also reduces CRH receptor type 2 mRNA expression, although the effect was not as marked as with IL-1alpha. However, CRH receptor type 2 mRNA expression is not altered in adult mouse ventricular cardiomyocytes stimulated in vitro with TNFalpha or IL-1alpha. 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.