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J Immunol. 2018 Jan 15;200(2):725-736. doi: 10.4049/jimmunol.1601808. Epub 2017 Dec 13.

mPGES1-Dependent Prostaglandin E2 (PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2 Production.

Author information

1
Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202.
2
Department of Pharmacology, Kitasato University, Tokyo 108-8641, Japan.
3
University of Kentucky Medical Center, Lexington, KY 40536; and.
4
Division of Rheumatology, University of Tennessee, Memphis, TN 38104.
5
Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202; leslie.j.crofford@vanderbilt.edu.

Abstract

The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE2, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE2 levels and is highly expressed at sites of inflammation. PGE2 is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4+ regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1-/- CD4+ cells showed impaired IL-17A, IFN-γ, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE2 by cocultured APCs synergized with that of Ag-experienced CD4+ T cells, with mPGES1 competence in the APC compartment enhancing CD4+ IL-17A and IFN-γ responses. However, in contrast with CD4+ cells that were Ag primed in vivo, exogenous PGE2 inhibited proliferation and skewed IL-17A to IFN-γ production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE2 production that impacts effector T cell IL-17A and IFN-γ responses.

PMID:
29237778
PMCID:
PMC5760456
DOI:
10.4049/jimmunol.1601808
[Indexed for MEDLINE]
Free PMC Article

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