Knockout of MAPK Phosphatase-1 Exaggerates Type I IFN Response during Systemic Escherichia coli Infection

We have previously shown that Mkp-1-deficient mice produce elevated TNF-alpha, 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. coli-infected wild-type and Mkp-1(-/-) mice. A large number of IFN-stimulated genes were more robustly expressed in E. coli-infected Mkp-1(-/-) mice than in wild-type mice. Multiplex analysis of the serum cytokine levels revealed profound increases in IFN-beta, IFN-gamma, TNF-alpha, IL-1 alpha and beta, IL-6, IL-10, IL-17A, IL-27, and GMSF levels in E. coli-infected Mkp-1(-/-) mice relative to wild-type mice. Administration of a neutralizing Ab against the receptor for type I IFN to Mkp-1(-/-) mice prior to E. coli infection augmented mortality and disease severity. Mkp-1(-/-) bone marrow-derived macrophages (BMDM) produced higher levels of IFN-beta mRNA and protein than did wild-type BMDM upon treatment with LPS, E. coli, polyinosinic:polycytidylic acid, and herring sperm DNA. Augmented IFN-beta induction in Mkp-1(-/-) BMDM was blocked by a p38 inhibitor but not by an JNK inhibitor. Enhanced Mkp-1 expression abolished IFN-beta induction by both LPS and E. coli but had little effect on the IFN-beta promoter activity in LPS-stimulated RAW264.7 cells. Mkp-1 deficiency did not have an overt effect on IRF3/7 phosphorylation or IKK activation but modestly enhanced IFN-beta mRNA stability in LPS-stimulated BMDM. Our results suggest that Mkp-1 regulates IFN-beta production primarily through a p38-mediated mechanism and that IFN-beta plays a beneficial role in E. coli-induced sepsis.

Automated summary

Mkp-1-deficient mice show elevated inflammatory cytokines, increased mortality, and disease severity following E. coli infection. Further investigation reveals that Mkp-1 regulates IFN-beta production primarily through a p38-mediated mechanism, and IFN-beta plays a beneficial role in E. coli-induced sepsis.