title: IL-1alpha and TNFalpha down-regulate CRH receptor-2 mRNA expression in the mouse heart.
abstract: 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon 97201, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Coste
authors.forename: K A
authors.initials: KA
authors.lastname: Heldwein
authors.forename: S L
authors.initials: SL
authors.lastname: Stevens
authors.forename: E
authors.initials: E
authors.lastname: Tobar-Dupres
authors.forename: M P
authors.initials: MP
authors.lastname: Stenzel-Poore
mesh_terms: D000818:Animals; D002469:Cell Separation; D003345:Corticosterone / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D006352:Heart Ventricles; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D012149:Restraint, Physical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D054832:Urocortins
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D020033:Protein Isoforms; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D014409:Tumor Necrosis Factor-alpha; D054832:Urocortins; C518358:urocortin 2, mouse; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone