Journal article
Knockout of MAPK Phosphatase-1 Exaggerates Type I IFN Response during Systemic Escherichia coli Infection
The Journal of immunology (1950), Vol.206(12), pp.2966-2979
06/15/2021
DOI: 10.4049/jimmunol.2001468
PMID: 34039638
Abstract
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.
Copyright © 2021 by The American Association of Immunologists, Inc.
Details
- Title: Subtitle
- Knockout of MAPK Phosphatase-1 Exaggerates Type I IFN Response during Systemic Escherichia coli Infection
- Creators
- Sean G Kirk - Nationwide Children's HospitalParker R Murphy - Nationwide Children's HospitalXiantao Wang - National Institutes of HealthCharles J Cash - Nationwide Children's HospitalTimothy J Barley - Nationwide Children's HospitalBridget A Bowman - Case Western Reserve UniversityAbel J Batty - Nationwide Children's HospitalWilliam E Ackerman - University of Illinois ChicagoJian Zhang - University of Iowa, PathologyLeif D Nelin - Nationwide Children's HospitalMarkus Hafner - National Institutes of HealthYusen Liu - Nationwide Children's Hospital
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.206(12), pp.2966-2979
- DOI
- 10.4049/jimmunol.2001468
- PMID
- 34039638
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: AI124029; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: AI142885; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: AI121196
- Language
- English
- Date published
- 06/15/2021
- Academic Unit
- Pathology
- Record Identifier
- 9984195952502771
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