Abstract
The central nervous dysfunctions of lethargy, fever and anorexia are manifestations of sepsis that seem to be mediated by increased cytokine production. Here we demonstrate that tumor necrosis factor (TNF)-α, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling. The stabilization of RGS7 by TNF-α requires activation of the stress-activated protein kinase p38 and the presence of candidate mitogen-activated protein kinase phosphorylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-α, a response that is nearly abrogated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.
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Acknowledgements
We would like to thank A. Goldberg for advice on this manuscript. T.B. was supported by a fellowship of the Deutsche Forschungsgemeinschaft (DFG). This work was supported by NIH-RO1 DK52897 (G.W.) and PHS grant MH01147 (E.K.).
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Benzing, T., Brandes, R., Sellin, L. et al. Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function. Nat Med 5, 913–918 (1999). https://doi.org/10.1038/11354
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DOI: https://doi.org/10.1038/11354
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