Classic interleukin-6 receptor signaling and interleukin-6 trans-signaling differentially control angiotensin II-dependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy in vivo.
Interleukin (IL)-6 acts via a receptor complex consisting of the cognate IL-6 receptor (IL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). Here, we investigated the role of these IL-6R components in hypertension and vascular hypertrophy in mice. Angiotensin (Ang) II (1.1 mg/kg/day) caused hypertension and cardiac/aortic hypertrophy in wild-type, but not IL-6(-/-), mice throughout 7 days. A recombinant dimeric soluble gp130 (sgp130Fc; 50 to 100 microg, i.p.) blocked Ang II hypertension but not hypertrophy in wild-type mice. Cognate IL-6R was detected in aortic smooth muscle, but its levels and those of plasma sIL-6R were approximately 50% decreased in IL-6(-/-) mice. Ang II infusion activated signal transducer and activator of transcription-3 in heart of WT and decreased Ang II receptor 1 (ATR1) expression in aorta. Both responses were unaffected by sgp130Fc and absent in IL-6(-/-) mice. In summary, we show that IL-6 trans-signaling is required for Ang II-dependent hypertension, but that hypertrophy, down-regulation of AT1R, and cardiac signal transducer and activator of transcription-3 activation are mediated via cognate IL-6R. These data show that IL-6 responses in a single disease context are governed by both modes of IL-6 signaling, with each pathway eliciting different outcomes. Inhibition of IL-6 signaling is suggested as a potential therapy for hypertension and cardiac hypertrophy.
Coles
Barbara
B
Dept of Medical Biochemistry and Immunology, Heath Park, Cardiff, UK.
Fielding
Ceri A
CA
Rose-John
Stefan
S
Scheller
Jürgen
J
Jones
Simon A
SA
O'Donnell
Valerie B
VB
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001794:Blood Pressure / Q000235:genetics; D006332:Cardiomegaly / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism*; D006984:Hypertrophy / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics* / Q000502:physiology; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000097:blood / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D000804:Angiotensin II; C519852:olamkicept