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Shedding of the tumor necrosis factor (TNF) receptor from the surface of hepatocytes during sepsis limits inflammation through cGMP signaling

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Science Signaling  27 Jan 2015:
Vol. 8, Issue 361, pp. ra11
DOI: 10.1126/scisignal.2005548

Taming TNF during sepsis

The proinflammatory cytokine tumor necrosis factor (TNF) is required for an effective immune response to invading pathogens; however, excessive TNF signaling through its receptor TNFR leads to cell death and tissue damage, such as occurs during sepsis. The proteolytic shedding of TNFR from the cell surface decreases TNF signaling in cells and reduces TNF concentrations in the plasma. Deng et al. showed that treating mouse or human hepatocytes with the bacterial product LPS resulted in increased shedding of TNFR by the protease TACE, an event dependent on the second messenger cGMP. Treating mice that had sepsis with drugs that increased the plasma concentration of cGMP decreased inflammation and increased survival, suggesting that a similar strategy might provide a therapy against sepsis in humans.

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