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Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function

Nature Medicine volume 5, pages 913–918 (1999)Cite this article

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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Figure 1: Increased accumulation of RGS7 induced by TNF-α.
Figure 2: Stabilization of RGS7 induced by TNF-α depends on candidate MAPK sites in Q170 and P248.
Figure 3: Activation of mitogen-activated protein kinase p38 is required for TNF-induced upregulation of RGS7.
Figure 4: Dominant-negative mutants of MEK1, ERK1/2, and PKC isozymes fail to suppress the TNF-mediated upregulation of RGS7.
Figure 5: LPS and TNF-α increase RGS7 protein levels in mouse brain.

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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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Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts, 02215, USA

    Thomas Benzing, Lorenz Sellin, Bernhard Schermer & Gerd Walz

  2. Institute for Cardiovascular Physiology, University Hospital of Frankfurt, Frankfurt, D-60590, Germany

    Ralf Brandes

  3. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Stewart Lecker

  4. Department of Psychiatry, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Emily Kim

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  1. Thomas Benzing
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Correspondence to Emily Kim.

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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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