MPGES1-Dependent Prostaglandin E 2 (PGE 2 ) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE 2 Production

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE 2 , 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 PGE 2 levels and is highly expressed at sites of inflammation. PGE 2 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 2/2 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 PGE 2 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 PGE 2 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 PGE 2 production that impacts effector T cell IL-17A and IFN-g responses.

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

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Prostaglandins E
Antigens
Interleukin-17
Regulatory T-Lymphocytes
T-Lymphocytes
Inflammation
Interleukin-23
Th17 Cells
Collagen Type II
Eicosanoids
Autoimmunity
Mental Competency
Immunization
Interleukin-6
Lymph Nodes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

MPGES1-Dependent Prostaglandin E 2 (PGE 2 ) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE 2 Production . / Maseda, Damian; Johnson, Elizabeth M.; Nyhoff, Lindsay E.; Baron, Bridgette; Kojima, Fumiaki; Wilhelm, Ashley J.; Ward, Martin R.; Woodward, Jerold G.; Brand, David; Crofford, Leslie J.

In: Journal of Immunology, Vol. 200, No. 2, 15.01.2018, p. 725-736.

Research output: Contribution to journalArticle

Maseda, D, Johnson, EM, Nyhoff, LE, Baron, B, Kojima, F, Wilhelm, AJ, Ward, MR, Woodward, JG, Brand, D & Crofford, LJ 2018, ' MPGES1-Dependent Prostaglandin E 2 (PGE 2 ) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE 2 Production ', Journal of Immunology, vol. 200, no. 2, pp. 725-736. https://doi.org/10.4049/jimmunol.1601808
Maseda, Damian ; Johnson, Elizabeth M. ; Nyhoff, Lindsay E. ; Baron, Bridgette ; Kojima, Fumiaki ; Wilhelm, Ashley J. ; Ward, Martin R. ; Woodward, Jerold G. ; Brand, David ; Crofford, Leslie J. / MPGES1-Dependent Prostaglandin E 2 (PGE 2 ) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE 2 Production In: Journal of Immunology. 2018 ; Vol. 200, No. 2. pp. 725-736.
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AU - Johnson, Elizabeth M.

AU - Nyhoff, Lindsay E.

AU - Baron, Bridgette

AU - Kojima, Fumiaki

AU - Wilhelm, Ashley J.

AU - Ward, Martin R.

AU - Woodward, Jerold G.

AU - Brand, David

AU - Crofford, Leslie J.

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N2 - The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE 2 , 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 PGE 2 levels and is highly expressed at sites of inflammation. PGE 2 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 2/2 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 PGE 2 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 PGE 2 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 PGE 2 production that impacts effector T cell IL-17A and IFN-g responses.

AB - The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE 2 , 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 PGE 2 levels and is highly expressed at sites of inflammation. PGE 2 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 2/2 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 PGE 2 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 PGE 2 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 PGE 2 production that impacts effector T cell IL-17A and IFN-g responses.

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