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

The central nervous dysfunctions of lethargy, fever and anorexia are manife stations of sepsis that seem to be mediated by increased cytokine productio n. Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent de gradation of RGS7, a regulator of C-protein signaling. The stabilization of RGS7 by TNF-alpha requires activation of the stress-activated protein kina se p38 and the presence of candidate mitogen-activated protein kinase phosp horylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-alpha, a response that is nearly abrog ated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediate d upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.