The function of MAP kinase phosphatase‐1 in Gram‐negative sepsis

Abstract

MAP kinase phosphatase (Mkp)‐1 acts as a feedback control mechanism that attenuates p38 and JNK in innate immune cells exposed to Toll‐like receptor (TLR) ligands. We have previously demonstrated that mice deficient in Mkp‐1 gene are highly sensitive to bacterial products including lipopolysaccharide (LPS) and more readily succumb to shock and multi‐organ failure. However, the role of Mkp‐1 in the immune responses to actual Gram‐negative bacteria remains unclear. We investigated the role of Mkp‐1 during Gram‐negative sepsis using Mkp‐1 knockout mice and E. coli as a model system. Compared to wild type mice, Mkp‐1 knockout exhibited earlier and greater mortality after infected intravenously with live E. coli. Histological analysis revealed more severe pulmonary edema and markedly hemoconcentration in the knockout mice than in the wild type mice. Interestingly, plasma from the infected wild type mice, but not those from the infected Mkp‐1 knockout mice, exhibited hyperlipidemia. Surprisingly, the Mkp‐1 knockout mice had a substantially greater bacterial burden than did the wild type mice in both the blood and spleens of the knockout mice. Gentamicin prevented mortality in wild type mice but had no effect on Mkp‐1 knockout mice. Our results indicate that Mkp‐1 is a crucial immune regulator determining the prognosis after infection and plays an important role in host defense far beyond simply regulating cytokine production.