scholarly journals Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling

2009 ◽  
Vol 206 (3) ◽  
pp. 535-548 ◽  
Author(s):  
Katia Boniface ◽  
Kristian S. Bak-Jensen ◽  
Ying Li ◽  
Wendy M. Blumenschein ◽  
Mandy J. McGeachy ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Prostaglandin E2 ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Retinoic Acid Receptor ◽  
Receptor Expression ◽  
Orphan Receptor ◽  
Antiinflammatory Drugs ◽  
Inflammatory Microenvironment ◽  
Ep4 Receptor

Prostaglandins, particularly prostaglandin E2 (PGE2), play an important role during inflammation. This is exemplified by the clinical use of cyclooxygenase 2 inhibitors, which interfere with PGE2 synthesis, as effective antiinflammatory drugs. Here, we show that PGE2 directly promotes differentiation and proinflammatory functions of human and murine IL-17–producing T helper (Th17) cells. In human purified naive T cells, PGE2 acts via prostaglandin receptor EP2- and EP4-mediated signaling and cyclic AMP pathways to up-regulate IL-23 and IL-1 receptor expression. Furthermore, PGE2 synergizes with IL-1β and IL-23 to drive retinoic acid receptor–related orphan receptor (ROR)-γt, IL-17, IL-17F, CCL20, and CCR6 expression, which is consistent with the reported Th17 phenotype. While enhancing Th17 cytokine expression mainly through EP2, PGE2 differentially regulates interferon (IFN)-γ production and inhibits production of the antiinflammatory cytokine IL-10 in Th17 cells predominantly through EP4. Furthermore, PGE2 is required for IL-17 production in the presence of antigen-presenting cells. Hence, the combination of inflammatory cytokines and noncytokine immunomodulators, such as PGE2, during differentiation and activation determines the ultimate phenotype of Th17 cells. These findings, together with the altered IL-12/IL-23 balance induced by PGE2 in dendritic cells, further highlight the crucial role of the inflammatory microenvironment in Th17 cell development and regulation.

scholarly journals Mycobacterium tuberculosis RpfE-Induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation

2021 ◽  
Vol 22 (14) ◽  
pp. 7535
Author(s):  
Hye-Soo Park ◽  
Seunga Choi ◽  
Yong-Woo Back ◽  
Kang-In Lee ◽  
Han-Gyu Choi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Cell Differentiation ◽  
Prostaglandin E2 ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Bacterial Load ◽  
Cell Responses ◽  
Ep4 Receptor ◽  
Th17 Cell Differentiation

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.

scholarly journals Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling

2009 ◽  
Vol 184 (6) ◽  
pp. i16-i16
Author(s):  
Katia Boniface ◽  
Kristian S. Bak-Jensen ◽  
Ying Li ◽  
Wendy M. Blumenschein ◽  
Mandy J. McGeachy ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cyclic Amp ◽  
Prostaglandin E2 ◽  
Th17 Cell ◽  
Receptor Signaling ◽  
Ep4 Receptor ◽  
Th17 Cell Differentiation ◽  
And Function

scholarly journals Mycobacterium Tuberculosis RpfE-induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation

2021 ◽  
Author(s):  
Hye-Soo Park ◽  
Seunga Choi ◽  
Yong Woo Back ◽  
Kang-In Lee ◽  
Han-Gyu Choi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Cell Differentiation ◽  
Prostaglandin E2 ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Bacterial Load ◽  
Cell Responses ◽  
Ep4 Receptor ◽  
Th17 Cell Differentiation

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.

scholarly journals Xianfanghuomingyin, a Chinese Compound Medicine, Modulates the Proliferation and Differentiation of T Lymphocyte in a Collagen-Induced Arthritis Mouse Model

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Bo Nie ◽  
Xue Li ◽  
Yi Wei ◽  
Meng Chen ◽  
Jingwei Zhou ◽  
...  
Keyword(s):  
Mouse Model ◽  
Th17 Cells ◽  
Retinoic Acid Receptor ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Cartilage Destruction ◽  
Orphan Receptor ◽  
Th2 Cells ◽  
Collagen Induced Arthritis ◽  
Proliferation And Differentiation

In traditional Chinese medicine (TCM), xianfanghuomingyin (XFHM) is used to treat autoimmune diseases, including rheumatoid arthritis (RA). Here, we studied the mechanisms underlying its treatment effects, especially its anti-inflammatory effects in a collagen-induced arthritis (CIA) mouse model. We found that cartilage destruction and pannus formation were alleviated by treatment with XFHM. The abnormal differentiation of Th1 and Th17 cells was downregulated significantly by XFHM, and Th2 and Treg cells were upregulated. Moreover, the expression levels of specific cytokines and transcription factors related to Th1 cells (interferonγ[IFNγ], T-bet) and Th17 cells (interleukin- [IL-] 17) and the nuclear receptor retinoic acid receptor-related orphan receptor-gamma (RORγ) were downregulated. Serum IL-4 and GATA-3, which contribute to Th2 cells differentiation, increased significantly after XFHM administration. These results indicate that XFHM can restore the balance of T lymphocytes and reestablish the immunological tolerance to inhibit autoinflammatory disorder of RA. Taken together, XFHM can be used as a complementary or alternative traditional medicine to treat RA.

scholarly journals Regulating human Th17 cells via differential expression of IL-1 receptor

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 530-540 ◽  
Author(s):  
Won-Woo Lee ◽  
Seong Wook Kang ◽  
Jihoon Choi ◽  
Seung-Hyun Lee ◽  
Kamini Shah ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Differential Expression ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Receptor Expression ◽  
Th17 Cell Differentiation ◽  
Memory Cd4 T Cells

Abstract In humans, interleukin-1β (IL-1β) has been suggested as an essential cytokine for developing IL-17– or IL-17A–producing CD4+ T helper 17 (Th17) cells. However, little is known about the relationship of IL-1 receptor expression and Th17 cell differentiation. We report here the presence of 2 distinct CD4+ T-cell populations with and without expression of IL-1RI that correlates with the capacity to produce IL-17 in naive and memory CD4+ T cells of human peripheral blood. IL-1RI+ memory CD4+ T cells had increased gene expression of IL17, RORC, and IRF4 even before T-cell receptor triggering, indicating that the effect of IL-1β is programmed in these cells via IL-1RI. Although CD4+ T cells from umbilical cord blood did not express IL-1RI, the cytokines IL-7, IL-15, and transforming growth factor-β (TGF-β) up-regulated IL-1RI expression on naive CD4+ T cells, suggesting that IL-1RI+ naive CD4+ T cells develop in periphery. Furthermore, IL-17 production from the cytokine-treated naive CD4+ T cells was induced by IL-1β and this induction was blocked by IL-1R antagonist. These results indicate that human Th17 cell differentiation is regulated via differential expression of IL-1RI, which is controlled by IL-7 and IL-15.

scholarly journals Interleukin (IL)-12 and IL-18 Synergize to Promote MAIT Cell IL-17A and IL-17F Production Independently of IL-23 Signaling

2020 ◽  
Vol 11 ◽  
Author(s):  
Suzanne Cole ◽  
Janine Murray ◽  
Catherine Simpson ◽  
Remi Okoye ◽  
Kerry Tyson ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Cell Activation ◽  
Retinoic Acid Receptor ◽  
Γδ T Cells ◽  
Lymphoid Cells ◽  
Orphan Receptor ◽  
Mait Cells ◽  
Activation Assay ◽  
Mait Cell

IL-23 is considered a critical regulator of IL-17 in Th17 cells; however, its requirement for inducing IL-17 production in other human immune subsets remains incompletely understood. Mucosal associated invariant T (MAIT) cells uniformly express retinoic acid receptor-related orphan receptor gamma t (RORγt) but only a minor population have been shown to produce IL-17A. Here we show that IL-17F is the dominant IL-17 isoform produced by MAIT cells, not IL-17A. For optimal MAIT cell derived IL-17A and IL-17F production, T cell receptor (TCR) triggering, IL-18 and monocyte derived IL-12 signaling is required. Unlike Th17 cells, this process is independent of IL-23 signaling. Using an in vitro skin cell activation assay, we demonstrate that dual neutralization of both IL-17A and IL-17F resulted in greater suppression of inflammatory proteins than inhibition of IL-17A alone. Finally, we extend our findings by showing that other innate-like lymphocytes such as group 3 innate lymphoid cells (ILC3) and gamma delta (γδ) T cells are also capable of IL-23 independent IL-17A and IL-17F production. These data indicate both IL-17F and IL-17A production from MAIT cells may contribute to tissue inflammation independently of IL-23, in part explaining the therapeutic disconnect between targeting IL-17 or IL-23 in certain inflammatory diseases.

scholarly journals The prostaglandin E2/EP4 receptor/cyclic AMP/T-type Ca2+ channel pathway mediates neuritogenesis in sensory neuron-like ND7/23 cells

2016 ◽  
Vol 130 (3) ◽  
pp. 177-180 ◽  
Author(s):  
Kenji Mitani ◽  
Fumiko Sekiguchi ◽  
Takashi Maeda ◽  
Yukari Tanaka ◽  
Shigeru Yoshida ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Prostaglandin E2 ◽  
Sensory Neuron ◽  
Ep4 Receptor

scholarly journals SOX-5 activates a novel RORγt enhancer to facilitate experimental autoimmune encephalomyelitis by promoting Th17 cell differentiation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Tian ◽  
Chao Han ◽  
Zhiyuan Wei ◽  
Hui Dong ◽  
Xiaohe Shen ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Orphan Receptor ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Cell Differentiation ◽  
Th17 Differentiation ◽  
Transcription 3 ◽  
Experimental Autoimmune

AbstractT helper type 17 (Th17) cells have important functions in the pathogenesis of inflammatory and autoimmune diseases. Retinoid-related orphan receptor-γt (RORγt) is necessary for Th17 cell differentiation and functions. However, the transcriptional regulation of RORγt expression, especially at the enhancer level, is still poorly understood. Here we identify a novel enhancer of RORγt gene in Th17 cells, RORCE2. RORCE2 deficiency suppresses RORγt expression and Th17 differentiation, leading to reduced severity of experimental autoimmune encephalomyelitis. Mechanistically, RORCE2 is looped to RORγt promoter through SRY-box transcription factor 5 (SOX-5) in Th17 cells, and the loss of SOX-5 binding site in RORCE abolishes RORCE2 function and affects the binding of signal transducer and activator of transcription 3 (STAT3) to the RORγt locus. Taken together, our data highlight a molecular mechanism for the regulation of Th17 differentiation and functions, which may represent a new intervening clue for Th17-related diseases.

scholarly journals Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine

2012 ◽  
Vol 209 (2) ◽  
pp. 251-258 ◽  
Author(s):  
Michael H. Shaw ◽  
Nobuhiko Kamada ◽  
Yun-Gi Kim ◽  
Gabriel Núñez
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
Steady State ◽  
Th17 Cells ◽  
Retinoic Acid Receptor ◽  
Selective Reduction ◽  
Orphan Receptor ◽  
Therapeutic Implications ◽  
Myd88 Signaling ◽  
Myeloid Differentiation Factor

TH17 cells are a lineage of CD4+ T cells that are critical for host defense and autoimmunity by expressing the cytokines IL-17A, IL-17F, and IL-22. A feature of TH17 cells at steady state is their ubiquitous presence in the lamina propria of the small intestine. The induction of these steady-state intestinal TH17 (sTH17) cells is dependent on the presence of the microbiota. However, the signaling pathway linking the microbiota to the development of intestinal sTH17 cells remains unclear. In this study, we show that IL-1β, but not IL-6, is induced by the presence of the microbiota in intestinal macrophages and is required for the induction of sTH17 cells. In the absence of IL-1β–IL-1R or MyD88 signaling, there is a selective reduction in the frequency of intestinal sTH17 cells and impaired production of IL-17 and IL-22. Myeloid differentiation factor 88–deficient (MyD88−/−) and germ-free (GF) mice, but not IL-1R−/− mice, exhibit impairment in IL-1β induction. Microbiota-induced IL-1β acts directly on IL-1R–expressing T cells to drive the generation of sTH17 cells. Furthermore, administration of IL-1β into GF mice induces the development of retinoic acid receptor–related orphan receptor γt–expressing sTH17 cells in the small intestine, but not in the spleen. Thus, commensal-induced IL-1β production is a critical step for sTH17 differentiation in the intestine, which may have therapeutic implications for TH17-mediated pathologies.

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