Journal article
Mitogen-Activated Protein Kinase Phosphatase-1 Controls PD-L1 Expression by Regulating Type I Interferon during Systemic Escherichia coli Infection
The Journal of biological chemistry, Vol.298(5), 101938
04/13/2022
DOI: 10.1016/j.jbc.2022.101938
PMCID: PMC9108994
PMID: 35429501
Abstract
Mitogen-activated protein kinase phosphatase (Mkp)a-1 knockout (KO) mice produce elevated cytokines and exhibit increased mortality and bacterial burden following systemic E. coli infection. To understand how Mkp-1 affects immune defense, we analyzed the RNA sequencing (RNA-seq) datasets previously generated from control and E. coli-infected Mkp-1+/+ and Mkp-1-/- mice. We found that E. coli infection markedly induced Programmed death-ligand 1 (PD-L1) expression, and that Mkp-1 deficiency further amplified PD-L1 expression. Administration of a PD-L1-neutralizing monoclonal antibody (mAb) to Mkp-1-/- mice increased the mortality of the animals following E. coli infection, although bacterial burden was decreased. Additionally, the PD-L1-neutralizing mAb increased serum interferon (IFN)-γ and tumor necrosis factor (TNF)-α, as well as lung and liver inducible nitric oxide synthase (iNOS) levels, suggesting an enhanced inflammatory response. Interestingly, neutralization of IFN-α/β receptor 1 (IFNAR1) blocked PD-L1 induction in Mkp-1-/- mice following E. coli infection. PD-L1 was potently induced in macrophages by E. coli and lipopolysaccharide (LPS) in vitro, and Mkp-1 deficiency exacerbated PD-L1 induction with little effect on the half-life of PD-L1 mRNA. In contrast, inhibitors of Janus kinase (JAK) 1/2 and Tyrosine kinase (TYK) 2, as well as the IFNAR1-neutralizing mAb, markedly attenuated PD-L1 induction. These results suggest that the beneficial effect of type I IFNs in E. coli-infected Mkp-1-/- mice is, at least in part, mediated by JAK/Signal transducer and activator of transcription (STAT)-driven PD-L1 induction. Our studies also support the notion that enhanced PD-L1 expression contributes to the bactericidal defect of Mkp-1-/- mice.
Details
- Title: Subtitle
- Mitogen-Activated Protein Kinase Phosphatase-1 Controls PD-L1 Expression by Regulating Type I Interferon during Systemic Escherichia coli Infection
- Creators
- Timothy J Barley - Nationwide Children's HospitalParker R Murphy - Nationwide Children's HospitalXiantao Wang - National Institutes of HealthBridget A Bowman - Nationwide Children's HospitalJustin M Mormol - Nationwide Children's HospitalCarli E Mager - Nationwide Children's HospitalSean G Kirk - Nationwide Children's HospitalCharles J Cash - Nationwide Children's HospitalSarah C Linn - The Ohio State UniversityXiaomei Meng - Nationwide Children's HospitalLeif D Nelin - The Ohio State UniversityBernadette Chen - The Ohio State UniversityMarkus Hafner - National Institutes of HealthJian Zhang - University of IowaYusen Liu - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.298(5), 101938
- DOI
- 10.1016/j.jbc.2022.101938
- PMID
- 35429501
- PMCID
- PMC9108994
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases
- Language
- English
- Date published
- 04/13/2022
- Academic Unit
- Pathology
- Record Identifier
- 9984244859802771
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