We have previously shown that Mkp-1deficient mice produce elevated TNF-a, IL-6, and IL-10 following systemic Escherichia coli infection, and they exhibited increased mortality, elevated bacterial burden, and profound metabolic alterations. To understand the function of Mkp-1 during bacterial infection, we performed RNA-sequencing analysis to compare the global gene expression between E. coliinfected wild-type and Mkp-1 2/2 mice. A large number of IFN-stimulated genes were more robustly expressed in E. coliinfected Mkp-1 2/2 mice than in wild-type mice. Multiplex analysis of the serum cytokine levels revealed profound increases in IFN-b, IFN-g, TNF-a, IL-1a and b, IL-6, IL-10, IL-17A, IL-27, and GMSF levels in E. coliinfected Mkp-1 2/2 mice relative to wildtype mice. Administration of a neutralizing Ab against the receptor for type I IFN to Mkp-1 2/2 mice prior to E. coli infection augmented mortality and disease severity. Mkp-1 2/2 bone marrowderived macrophages (BMDM) produced higher levels of IFN-b mRNA and protein than did wild-type BMDM upon treatment with LPS, E. coli, polyinosinic:polycytidylic acid, and herring sperm DNA. Augmented IFN-b induction in Mkp-1 2/2 BMDM was blocked by a p38 inhibitor but not by an JNK inhibitor. Enhanced Mkp-1 expression abolished IFN-b induction by both LPS and E. coli but had little effect on the IFN-b promoter activity in LPSstimulated RAW264.7 cells. Mkp-1 deficiency did not have an overt effect on IRF3/7 phosphorylation or IKK activation but modestly enhanced IFN-b mRNA stability in LPS-stimulated BMDM. Our results suggest that Mkp-1 regulates IFN-b production primarily through a p38-mediated mechanism and that IFN-b plays a beneficial role in E. coliinduced sepsis.

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