Blockade of multiple but not single cytokines abrogates downregulation of angiotensin II type-I receptors and anticipates septic shock

In this prospective, randomized animal study, the role of proinflammatory cytokines in the pathogenesis sepsis-induced circulatory failure with downregulation of angiotensin-II-type-I-(AT1)-receptors was investigated. Sepsis in wild-type mice and in mice with deficiencies for TNF-α, IL-1β, IFN-γ or IL-6 was induced by cecal ligation and puncture (CLP) and wild-type mice were injected with cytokines. Animals were treated with glucocorticoids or small interfering RNA (siRNA) targeting single or multiple cytokines or NF-κB. Vascular smooth muscle cells (VSMCs) were incubated with cytokines. CLP resulted in circulatory failure and a significant downregulation of AT1-receptors. Injection of single proinflammatory cytokines also strongly downregulated AT1-receptors paralleled by a markedly endogenous liberation of further cytokines, whereas, simultaneous blockade of these endogenously activated cytokines by dexamethasone prevented downregulation of AT1-receptors. Furthermore, inhibition of multiple but not single cytokines by treatment with siRNA against multiple cytokines or NF-κB significantly attenuated CLP-induced AT1-receptor downregulation and prevented septic circulatory failure. Our data demonstrate that downregulation of AT1-receptors during sepsis is due to multiple but not single cytokines and define a relevant role for NF-κB in the pathogenesis of septic shock.