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

Coles, Barbara, Fielding, Ceri Alan ORCID: https://orcid.org/0000-0002-5817-3153, Rose-John, Stefan, Scheller, J., Jones, S. A. and O'Donnell, Valerie Bridget ORCID: https://orcid.org/0000-0003-4089-8460 2007. 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. American Journal of Pathology 171 (1) , pp. 315-325. 10.2353/ajpath.2007.061078

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General) R Medicine > RZ Other systems of medicine
Publisher:	American Society for Investigative Pathology
ISSN:	0002-9440
Last Modified:	31 Jan 2025 22:24
URI:	https://orca.cardiff.ac.uk/id/eprint/67733

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