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Keywords:

  • prostanoid;
  • prostanoid receptor;
  • knockout mice;
  • T cell subset;
  • immune diseases

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. Acknowledgements
  5. REFERENCES

Three distinct subsets of T helper (Th) cells, Th1, Th2, and Th17, not only contribute to host defense against pathogens, but also cause many types of immune diseases. Differentiation and functions of these T cell subsets are mainly regulated by specific cytokines. Intriguingly, recent studies have revealed that prostanoids including various types of prostaglandins (PGs) and thromboxane (TX) are also involved in these processes. Prostanoids exert their actions by binding to their specific receptors. They include PGD receptor, EP1, EP2, EP3, and EP4 subtypes of PGE receptor, PGF receptor, PGI receptor, and TX receptor. From many in vitro findings, prostanoids, especially PGE2, were traditionally believed to be an immunosuppressant. However, studies using mice deficient in each type or subtype of prostanoid receptors and their selective agonists and antagonists have revealed that prostanoids collaborate with cytokines, and critically regulate T cell proliferation, differentiation and functions. Recent studies have revealed that PGE2 facilitates Th1 cell differentiation and Th17 cell expansion in collaboration with IL-12 and IL-23, respectively, and that these PGE2 actions contribute to development of immune diseases mediated by these Th subsets. Furthermore, studies using the receptor-deficient mice have also revealed that other prostanoids including PGD2 and PGI2 contribute to regulation of immune diseases of the Th2 type such as allergic asthma. These findings shed a new light on the roles of prostanoids in T cell-mediated immunity and immune diseases. © 2010 IUBMB IUBMB Life, 62(8): 591–596, 2010.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. Acknowledgements
  5. REFERENCES

The immune system defends the host by exerting a wide array of responses to invading pathogens and other noxious antigens. Upon invasion these foreign organisms and substances are ingested by antigen-presenting cells (APCs) such as dendritic cells and macrophages. APCs process them to migrate toward draining lymphnodes (LNs), and present there the processed antigens to naive T cells as a complex with MHC molecules. This triggers clonal expansion and differentiation of T cells, which determine the outcome of immune responses. There are two types of naïve T cells, CD4+ T cells (helper T, Th) and CD8+ T cells (cytotoxic T cells, Tc). Dependent on types of cytokines to which they are exposed during antigen presentation, CD4+ T cells differentiate into three distinct subsets of effector T cells, named Th1, Th2, and Th17 cells (1–3). Th1 cells are characterized by production of interleukin (IL)-2 and interferon (IFN)-γ, Th2 cells by production of IL-4, IL-5, IL-6, and IL-13, and Th17 cells by production of IL-17(A), IL-17F, and IL-22. Th1 cells are responsible for cell-mediated inflammatory reactions such as delayed type hypersensitivity, and are critical for eradication of intracellular pathogens, whereas Th2 cells are involved in optimal antibody production, particularly IgE and IgG1 subtypes, and elicit humoral immune response against extracellular pathogens. Th17 cells mediate host immune response against extracellular bacteria, some fungi, and other microbes, probably not well covered by Th1 and Th2 cells, and promote tissue inflammation. During antigen presentation, APCs produce a variety of cytokines and other mediators, and the composition of cytokines to which naive T cells are exposed directs T cell differentiation (1–3). IL-12 and IL-4 are crucial cytokines of T cell differentiation into Th1 and Th2 cells, respectively, and a combination of transforming growth factor-β (TGF-β) and IL-6 is a determinant of Th17 cells. In addition to these cytokines, recent studies have revealed that noncytokine substances such as prostanoids are also involved in these processes.

Prostanoids, including prostaglandin (PG) D2, PGE2, PGF, PGI2, and thromboxane (TX) A2 are lipid mediators with a variety of physiological actions produced in response to various extracellular stimuli (4). When cells are stimulated by extracellular stimuli, phospholipase A2 is activated, and releases arachidonic acid from cell membrane. Cyclooxygenase (COX) then converts arachidonic acid to PGH2, which is further converted to each prostanoid by the action of synthases specific for respective prostanoid (Fig. 1). Prostanoids exert their actions by binding to their cognate receptors termed DP for the PGD receptor, EP1, EP2, EP3, and EP4 subtypes of the PGE receptor, FP for the PGF receptor, IP for the PGI receptor, and TP for the TX receptor (Fig. 1). All of these receptors are G-protein coupled receptors (GPCRs) with seven transmembrane domains that couple to different types of G-proteins. While these receptors generally couple to more than one G protein and more than one signaling pathway, they are devided into three groups dependent on a major signaling pathway they initiate. The first group consisting of DP, EP2, EP4, and IP mainly couples to Gs and raises intracellular cyclic adenosine monophosphate (cAMP) concentration, the second group consisting of EP1, FP, and TP mainly raises intracellular free calcium ion concentration through a class of Gq proteins, and the third consisting of EP3 alone mainly couples to Gi and decreases intracellular cAMP concentration. These prostanoid receptors constitute a prostanoid receptor family within a superfamily of GPCRs. Furthermore, there is another GPCR for PGD2 termed CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), which belongs not to the prostanoid receptor family but the chemokine receptor family. As nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and indomethacin inhibit prostanoid synthesis, the roles of prostanoids in the body have classically been examined by the use of these drugs, and by adding exogenous prostanoids. These studies suggest that prostanoids work in a variety of processes such as fever generation, inflammation, and pain, but have little contribution to immune response. However, recently mice deficient in each prostanoid receptor were generated, and studies using these mice have revealed that porostanoids including PGE2 play important roles in the immune system. In this article, we critically review literatures on these roles of prostanoids emerging in the immune system, focusing on their roles in T cell-mediated immunity.

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Figure 1. Prostanoids and their receptors. Prostanoids are formed by sequential actions of COX and respective prostanoid synthases, and exert their actions by binding to their cognate receptors. (only main signaling pathways are described).

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Regulation of Th1 Cells by PGE2In Vitro; Studies From Past to Present

Actions of PGE2 in Th cells were examined from 1980s in vitro culture system. These studies showed that PGE2 suppresses proliferation, differentiation, cytokine production of Th1 cells, while it shows little effect against Th2 cells or rather enhances production of Th2 type cytokines (5–7). Because these actions on Th1 and Th2 cells are replicated by cAMP analogs such as dibutyryl cAMP (db-cAMP), it was believed that these effects of PGE2 on Th cells are cAMP dependent (7). Indeed, Nataraj et al. (8) used T cells from mice deficient in each subtype of PGE receptor, and showed that the Th1 suppressive effect of PGE2 is mediated via EP2 and EP4 receptor that couple to Gs to increase the intracellular cAMP level.

While suppression of Th1 response by PGE2 was thus thought to be a consequence of an increase in the intracellular cAMP level via EP2 and EP4, it became also known that the increase of cAMP competes at Lck activation with the signaling from TCR and/or costimulatory molecules, CD28, in T cells, and that the effect of PGE2 can be altered dependent on the strength of TCR stimulation (9, 10). Based on these findings, Yao et al. (11) examined the effect of PGE2 on Th1 differentiation with various strength of anti-CD28 antibody stimulation. They found that in the presence of weaker CD28 stimulation, PGE2 suppressed Th1 differentiation in a concentration-dependent manner as seen in the previous reports (5–8). Conversely, on stronger CD28 stimulation, PGE2 facilitates Th1 differentiation. They then used T cells from mice deficient in each EP subtype as well as selective agonists, and clarified that the Th1-facilitating effect of PGE2 under strong CD28 stimulation is mediated via the EP2 and EP4 receptor. They also analyzed intracellular signaling pathways, and found that the Th1-facilitating effect via EP2 and EP4 is dependent not on cAMP but on the PI3K pathway (Fig. 2). These results suggest that PGE2 uses the same receptors, EP2 and EP4, and either facilitates or suppresses Th1 differentiation through different signaling pathways (Fig. 2). However, whether such dual actions of PGE2 occur context-dependently in vivo, remains to be verified (see later).

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Figure 2. Facilitation of Th1 cell differentiation and Th17 cell expansion by PGE2-EP4 signaling. The PGE2-EP2/EP4 signaling regulates generation of Th subsets at least at three point, (1) Th1 differentiation, (2) IL-23 production by DCs, and (3) Th17 cell expansion.

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Facilitation of Th17 Expansion by PGE2In Vitro

Recently, Th17, a new-comer of Th subset, was identified, and involvement of Th17 cells in immune diseases such as rheumatoid arthritis, multiple sclerosis, and Crohn's disease, has been suggested. IL-6 and TGF-β initially differentiate naïve mouse T cells to Th17 cells. IL-23 then expands Th17 cells and stabilizes their phenotype (3). Yao et al. (11) examined the effect of PGE2 on differentiation and expansion of Th17 cells by using CD4+ T cells from mice. PGE2 suppressed Th17 cell differentiation from naïve T cells in the presence of TGF-β and IL-6 (Fig. 2). This suppressive effect of PGE2 on Th17 cell differentiation by TGF-β and IL-6 was also reported by Chen et al. (12). On the other hand, PGE2 concentration-dependently expanded Th17 cell population in the presence of IL-23 (11) (Fig. 2). Yao et al. (11) also clarified that this Th17-expanding effect of PGE2 is EP2- and EP4-dependent, but, different from the action on Th1 differentiation, is mediated by cAMP (Fig. 2). These results demonstrate that, although PGE2 uses the same receptors, EP2 and EP4, it uses different signaling pathways and regulates differentiation and/or expansion of different Th subsets in combination with different stimuli.

The effect of PGE2 on facilitation of Th17 cell expansion was also reported in human T cells. In human T cells, IL-1β and IL-23 are important for induction of Th17 cells. Boniface et al. (13) used human peripheral blood T cells and reported that PGE2 facilitates IL-17 production from differentiating Th17 cells in the presence of IL-1β and IL-23, and that this action is through induction of IL-1 receptor and IL-23 receptor by activation of the PGE2-EP2/EP4-cAMP pathway. They also found that PGE2 in combination with IL-1β and IL-23 induces expression of CCR6, a chemokine receptor preferentially expressed on Th17 cells. Similarly, Chizzolini et al. (14) demonstrated that PGE2 in combination with IL-23 facilitates Th17 cell expansion from CD4+CD45RO+ (memory) T cell population. On the other hand, PGE2 did not facilitate Th17 cell differentiation from CD4+CD45RO (naive) T cells, which is consistent with the finding of Yao et al. in mice (11). However, unlike Boniface et al., Chizzolini et al. showed that PGE2 can induce CCR6 without other cytokines. By using human peripheral blood T cells, Napolitani et al. (15) also reported similar Th17 cell expanding effect of PGE2 to those reported by Boniface et al. (13) and Chizzolini et al. (14).

Another important point regarding to the regulation of Th17 cells by PGE2 is that PGE2 facilitates IL-23 production by DCs (Fig. 2). Yao et al. (11) showed that IL-23 production from anti-CD40 antibody-stimulated DCs is further augmented by PGE2 or an EP4 agonist. They further found almost complete suppression of IL-23 production by both indomethacin and an EP4 antagonist under this condition. These results indicate that endogenous PGE2 plays an essential role in IL-23 production from anti-CD40 stimulated DCs. Consistently, the Ganea's group reported that exogenously added PGE2 in combination with Toll-like receptor ligands enhances the production of IL-23 by DCs (16, 17). These results demonstrate that PGE2 in combination with IL-23 facilitates Th17 expansion by activating cAMP pathway via the EP2 and EP4 receptor in differentiating Th17 cells. Further, the production of IL-23 itself is also regulated by PGE2 at least under some conditions.

Regulation of Th1/Th17-Mediated Immune Diseases by PGE2In Vivo

Several findings support that the facilitation of Th1 differentiation and Th17 expansion by PGE2 also operate in vivo. Yao et al. (11) used an EP4 antagonist, and examined the role of the PGE2-EP4 signaling in mouse contact hypersensitivity (CHS) and experimental autoimmune encephalomyelititis (EAE), both of which are mediated by Th1 and Th17 cells. They found that treatment of mice with the EP4 antagonist ameliorated the diseases in both models. Moreover, when they collected lymph node cells from the immunized mice and examined their responses to specific antigens, proliferation response and IFN-γ and IL-17 production were all significantly reduced in the cells from mice treated with the EP4 antagonist compared to those from the vehicle- treated control mice. These results suggest that the PGE2-EP4 signaling acts in immunization phase to induce Th1 differentiation and Th17 expansion in the body and blockade of this signaling leads to suppression of generation of antigen-specific Th1 and Th17 cells. Sheibanie et al. (18, 19) have also reported that exogenously administered PGE2 analogs such as misoprostol, an EP3/EP4 agonist, exacerbate both 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and collagen-induced arthritis in mice, and up-regulate expression of IL-23 and IL-17 at the lesions. These data demonstrate that PGE2 promotes development of Th1 and Th17 subsets in vivo. There is, however, a study showing an apparently opposite action of PGE2 in Th1 cell function in vivo. Kabashima et al. (20) used the dextran sodium sulfate (DSS)-induced colitis model which mimics ulcerative colitis, and found that treatment of mice with an EP4 antagonist resulted in increased accumulation of IFN-γ positive cells in the colon mucosa of mice with colitis compared to that of vehicle-treated mice with colitis. While these results may suggest that the PGE2-EP4 signaling functions to suppress Th1 cell proliferation in DSS-induced colitis, it should be mentioned that colitis in this model is caused by disruption of intestinal epithelial barrier and that the PGE2-EP4 signaling functions to protect it. Therefore, there remains a possibility that accumulation of IFN-γ positive cells in the colon mucosa is the secondary consequence of the disruption of intestinal barrier by the EP4 antagonism.

In addition to these EP2 and EP4 actions, Nagamachi et al. (21) showed EP1 is also involved in facilitation of Th1 cell differentiation under certain conditions. They found that Th1 response was impaired in EP1−/− mice in CHS model in which Th1 response is believed to be dominant. However, impaired Th1 response in EP1−/− mice was overcome by antigen application at high doses, which suggests that the role of EP1 is context-dependent. The impairment of Th1 response in EP1−/− was replicated by treatment with an EP1 selective antagonist of wild-type mice in immunization phase. Consistent with these in vivo finding, they showed that an EP1 selective agonist facilitates Th1 differentiation from naïve CD4+ T cells under the Th1-skewing conditions in vitro. In this case, facilitation of Th1 differentiation by EP1 occurs in the absence of costimulatory signaling such as CD28, reflecting the in vivo results in which CHS response in EP1−/− mice was impaired in suboptimal antigen stimulation. These results suggest that unlike cAMP, calcium signaling via EP1 functions as a booster of suboptimal condition for Th1 differentiation.

Although it is known that macrophages and DCs produce prostanoids including PGE2in vitro, there is poor evidence that these cells really produce prostanoids in vivo upon antigen presentation in lymph nodes. In their report, Nagamachi et al. (21) also reported up-regulation of inducible microsomal PGE synthase 1 (mPGES-1) in DCs in the draining lymph nodes after hapten application in the CHS model. At the same time, production of IL-12 by DCs in these lymph nodes was also observed. These results suggest that when naïve T cells receive antigen presentation by DCs in regional lymph nodes, activated DCs produce PGE2 and, possibly, other prostanoids including PGI2 and TXA2, and these prostanoids act on naïve T cells in collaboration with cytokines to induce T cell activation and differentiation. Consistent with these findings, Kihara et al. (22) have recently shown that the extent of EAE and development of Th17 cells are suppressed in mPGES-1−/− mice. However, while both the onset and the severity of EAE are suppressed by treatment with an EP4 antagonist, the peak of EAE is not different between mPGES-1−/− mice and WT mice, but suppression of EAE after the peak is greater in mPGES-1−/− mice compared to WT mice. Although impaired development of Th1 and Th17 cells in mPGES-1−/− mice is consistent with the results by Yao et al., the reason for different kinetics of the suppression remain currently unknown.

T cell regulatory roles are also seen in other prostanoids. Nakajima et al. (23) recently reported the role of the PGI2-IP signaling on Th1 differentiation. They used CHS model, and found that CHS response is impaired in IP−/− mice with decreased number of Th1 cells in lymph nodes. In addition, they showed that an IP agonist, iloprost, facilitates Th1 differentiation in the presence of high anti-CD28 stimulation in vitro. This action of the IP agonist was mimicked by db-cAMP and a PKA agonist, N6-Bnz-cAMP, indicating that the PGI2-IP signaling facilitates Th1 differentiation through the cAMP-PKA pathway. These results indicate that the cAMP signaling can facilitate but not suppress Th1 differentiation under certain conditions. In addition, a possibility of contribution by other signaling pathways is not excluded, because other signaling pathways such as PI response or modification of other molecules such as TRPV1 channel by phosphorylation are also evoked downstream of the IP receptor (24). Thus, facilitation of Th1 differentiation via IP through cAMP pathway is to be confirmed by further studies.

Other Immune Modulatory Actions of Prostanoids

Prostanoids also contribute to other aspects of immune response. By using the ovalbumin-induced allergic asthma model, Matsuoka et al. (25) found that accumulation of inflammatory cells such as eosinophils and lymphocytes in bronchial alveolar lavage (BAL) fluid was abrogated in DP−/− mice with reduced production of Th2 type cytokines, IL-4, IL-5, and IL-13. Conversely, Kunikata et al. (26) found that EP3−/− mice showed enhanced allergic asthma response including augmented accumulation of inflammatory cells and over-production of Th2 cytokines in BAL fluid in the same model. In both in DP−/− mice and EP3−/− mice, serum concentrations of antigen-specific IgE were similar to those of WT mice, indicating that these receptors regulate the allergic response at a step or steps subsequent to IgE synthesis. Both DP and EP3 are expressed in the airway epithelium of the challenged lung, and administration of an EP3 agonist to OVA sensitized WT mice ameliorate the symptom of asthma by suppressing expression of chemokines in the airway epithelial cells. Given that DP couples to Gs and EP3 couples to Gi, these results suggest that DP and EP3 expressed on the epithelium functionally antagonize each other in allergic asthma. In addition to these reports, augmented Th2 response including enhanced IgE and IgG1 production and, consequently, enhanced allergic inflammation in the asthma model were reported by Takahashi et al. (27) in IP−/− mice. This Th2 enhanced phenotype may reflect impaired Th1 response in IP−/− mice in CHS model reported by Nakajima et al (23). These results indicate that the PGI2-IP signaling facilitates Th1 response, and suppresses Th2 response.

Finally, TXA2 also plays several roles in the immune system in the body. Thymus is the organ where TP is abundantly expressed. Ushikubi et al. (28) previously reported that stimulation of TP on thymocytes induces apoptosis of these cells in vitro. Consistent with these finding, Rocha et al. (29) reported that the thymus of TP−/− mice shows resistance against LPS-induced thymocyte apoptosis. In addition to these finding on TP in the thymus, Kabashima et al. (30) found that the CHS response by DNFB is enhanced in TP−/− mice. They also found that stimulation of TP on naïve T cell facilitates chemokinesis of these cells, and suggested that this movement possibly disturbs DC-T cell interaction in initiation of immune response (30). On the basis of these results, they proposed that the TXA2-TP signaling functions as a negative regulator of DC-T cell interaction.

Future Perspectives

Figure 3 summarizes roles of prostanoids in T cell-mediated immunity we reviewed in this article. Recent studies have shown that, contrary to the previous belief that PGE2 works as an immunosuppressant, the PGE2-EP2/EP4 signaling works as an immunoactivator in pathological processes such as EAE and CHS. Furthermore, the PGE2-EP1 signaling, the PGE2-EP3 signaling, the PGI2-IP signaling, the TXA2-TP signaling, and the PGD2-DP signaling function in various aspect of immune response and modify diseases such as CHS and allergic asthma in vivo. It is important to correlate these immunomodulatory actions of prostanoids found in mice to their actions in immune diseases of humans. As to this point, the Th17 expanding effect of PGE2 has shown in both mouse and human T cells in vitro, and human EP4 gene was identified as a susceptible gene of Crohn's disease (31, 32), in which IL-23 and Th17 are believed to be involved. Furthermore, Oguma et al. (33) reported that SNPs of human DP gene affect transcription efficiency and are related to the susceptibility to asthma in humans. We expect much to follow on this line. Also shown here is that prostanoids function not alone but in combination with other signaling molecules, particularly cytokines, to regulate T cell differentiation, proliferation, and functions, to determine the outcome of diseases. Cross-talk between cytokine signaling and GPCR signaling of prostanoids underlie such collaboration and should be clarified on a molecule basis. We expect that future studies reveal further novel actions of prostanoids in immunity.

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Figure 3. Summary of roles of prostanoids in vivo in immune response. Actions of prostanoids in vivo in immune response reviewed in this article.

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Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. Acknowledgements
  5. REFERENCES

The authors thank Ono Pharmaceutical (Osaka, Japan) for supplying EP agonists and antagonist. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a grant from the National Institute of Biomedical Innovation of Japan.

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. Acknowledgements
  5. REFERENCES
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