Published online before print May 3, 2007

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(American Journal of Pathology. 2007;171:315-325.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061078

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

Barbara Coles^*, Ceri A. Fielding^*, Stefan Rose-John, Jürgen Scheller, Simon A. Jones^* and Valerie B. O’Donnell^*

From the Department of Medical Biochemistry and Immunology,^* Cardiff University, Cardiff, United Kingdom; and the Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

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 µg, 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 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.

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