MPGES1-Dependent Prostaglandin E2 (PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2 Production

Damian Maseda, Elizabeth M. Johnson, Lindsay E. Nyhoff, Bridgette Baron, Fumiaki Kojima, Ashley J. Wilhelm, Martin R. Ward, Jerold G. Woodward, David D. Brand, Leslie J. Crofford

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 mPGES12/2 CD4+ cells showed impaired IL-17A, IFN-g, 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-g responses. However, in contrast with CD4+ cells that were Ag primed in vivo, exogenous PGE2 inhibited proliferation and skewed IL-17A to IFN-g 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-g responses.

Original languageEnglish
Pages (from-to)725-736
Number of pages12
JournalJournal of Immunology
Volume200
Issue number2
DOIs
StatePublished - Jan 15 2018

Bibliographical note

Publisher Copyright:
Copyright © 2018 by The American Association of Immunologists, Inc.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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