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Knockout of MAPK Phosphatase-1 Exaggerates Type I IFN Response during Systemic Escherichia coli Infection.
journal contributionposted on 2022-11-01, 21:00 authored by Sean G Kirk, Parker R Murphy, Xiantao Wang, Charles J Cash, Timothy J Barley, Bridget A Bowman, Abel J Batty, William AckermanWilliam Ackerman, Jian Zhang, Leif D Nelin, Markus Hafner, Yusen Liu
We have previously shown that Mkp-1-deficient mice produce elevated TNF-α, 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-β, IFN-γ, TNF-α, IL-1α and β, 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-β mRNA and protein than did wild-type BMDM upon treatment with LPS, E. coli, polyinosinic:polycytidylic acid, and herring sperm DNA. Augmented IFN-β induction in Mkp-1 -/- BMDM was blocked by a p38 inhibitor but not by an JNK inhibitor. Enhanced Mkp-1 expression abolished IFN-β induction by both LPS and E. coli but had little effect on the IFN-β 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-β mRNA stability in LPS-stimulated BMDM. Our results suggest that Mkp-1 regulates IFN-β production primarily through a p38-mediated mechanism and that IFN-β plays a beneficial role in E. coli-induced sepsis.
CitationKirk, S. G., Murphy, P. R., Wang, X., Cash, C. J., Barley, T. J., Bowman, B. A., Batty, A. J., Ackerman, W. E., Zhang, J., Nelin, L. D., Hafner, M.Liu, Y. (2021). Knockout of MAPK Phosphatase-1 Exaggerates Type I IFN Response during Systemic Escherichia coli Infection. The Journal of Immunology, 206(12), 2966-2979. https://doi.org/10.4049/jimmunol.2001468
PublisherThe American Association of Immunologists
GeneticsInfectious Diseases2.1 Biological and endogenous factors1.1 Normal biological development and functioningInfection3 Good Health and Well BeingAnimalsCells, CulturedDual Specificity Phosphatase 1Escherichia coli InfectionsInterferon-betaMiceMice, Inbred C57BLMice, KnockoutRAW 264.7 Cellsp38 Mitogen-Activated Protein KinasesImmunologyImmunology