Biochemical and Biophysical Research Communications
IL-27 affects helper T cell responses via regulation of PGE2 production by macrophages
Introduction
IL-27 is a novel heterodimeric cytokine consisting of EBI-3 and p28 which are structurally related to the IL-12/IL-23 subunits p40 and p35/p19, respectively [1]. IL-27 is produced by activated antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages [2], [3], [4]. IL-27 signals through its heterodimeric receptor consisting of WSX-1 and gp130 [2], [3], [4]. Initial studies demonstrated that IL-27 plays a role in Th1 induction and enhances proliferation of naïve CD4+ T cells [1], [2], [3], [4]. Recent studies, however, have demonstrated the anti-inflammatory function of IL-27 by generating Tr1 cells [5]. In addition to its regulation of T cell function, IL-27 also regulates APCs in an autocrine manner [4].
Prostaglandins (PGs) are a group of biologically active lipid mediators that are derived from arachidonic acid, and mediate a variety of functions. While cyclooxygenase (COX)-1 constitutively exists and mediates PG production in various tissues/organs, COX-2 is induced in immune cells, such as macrophages, by stimulation including growth factors, and mediates PG production in inflammatory venues [6]. Among various PGs produced, PGE2 has a dominant role in inflammation/immune response [7], [8]. Interestingly, recent reports have demonstrated that PGE2 promotes Th1 differentiation and Th17 expansion in vitro via its receptors, EP2 and EP4 [9], [10]. Regulation of PGs, especially PGE2, may thus be a potent target of anti-inflammation strategies.
To date, functions of IL-27 on lipid mediators are poorly understood. In this study, we firstly demonstrated that lack of IL-27 signaling resulted in enhanced production of PGE2 by bone marrow-derived macrophages (BMDMs), which led to increased production of IL-17A and IFN-γ by CD4+ T cells. We also demonstrated that IL-27 negatively regulated COX-2 expression in a STAT1-dependent way. These findings clearly showed that IL-27 regulates PGE2 production by macrophages and “indirectly” regulates Th1/17 differentiation. IL-27 modulation of PGE2 production is a novel mechanism by which IL-27 shows its anti-inflammatory/immunosuppressive function.
Section snippets
Mice
Female WSX-1−/− mice were generated as described previously [11]. Female STAT1−/− mice were provided by Dr. Yoshimura (Keio University, Japan). C57BL/6J mice as a control were purchased from Japan CLEA, Inc. Mice were maintained under specific pathogen-free conditions and used between 8 and 14 weeks of age. All experiments were approved by the Animal Care and Use Committee at Nippon Boehringer Ingelheim Co., Ltd. or Saga University.
Reagents
Recombinant murine (rm) M-CSF was purchased from eBioscience.
WSX-1-deficient BMDM conditioned medium promoted IFN-γ and IL-17A secretion by CD4+ T cells
LPS stimulation of BMDMs induced expression of IL-27 subunits, EBI-3 (peak at around 12 h after stimulation) and p28 (peak as early as 3–6 h after stimulation) (Supplemental Fig. 1A). LPS stimulation also induced expression of WSX-1 (data not shown). LPS stimulation of macrophages not only induced IL-27R expression but also primed the cells responsive to IL-27 stimulation by STAT1 activation. IL-27 stimulation of LPS-pre-treated BMDMs, but not untreated BMDMs, induced phosphorylation of both
Discussion
Here we firstly reported that IL-27 negatively regulated PGE2 production from murine macrophages and it resulted in the modulation of IFN-γ and IL-17A production from CD4+ T cells in vitro.
In the present study, CM from WSX-1-deficient BMDMs after LPS stimulation induced higher amount of IFN-γ and IL-17A from CD4+ T cells (Fig. 1). WSX-1-deficient BMDMs produced higher level of PGE2 and cytokines such as IL-6 and IL-12p40, than control BMDMs, (Figs. 2A and 3). Inhibition of PGE2 production by
Acknowledgments
This study was supported in part by grants from the Ministry of Education, Science, Technology, Sports and Culture of Japan (H.Y. and H.H.). The authors are grateful to Drs. Akihiko Yoshimura and Christopher Hunter for helpful discussion and Ms. Furukawa for secretarial work.
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