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PGE 2 inhibits STAT3 phosphorylation. Purified CD4 + T cells were stimulated by immobilized Abs as indicated in the presence or absence of PGE 2. After 24 h, the level of p-Tyr STAT3 was determined by flow cytometry (representative of two independent experiments). (STAT3 staining: shaded gray areas; isotype control: black lines.)
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The ubiquitous protein CD46, a regulator of complement activity, promotes T cell activation and differentiation toward a regulatory Tr1-like phenotype. The CD46-mediated differentiation pathway is defective in several chronic inflammatory diseases, underlying the importance of CD46 in controlling T cell function and the need to understand its regul...
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... acquiring Foxp3 maintained CD46 expression although CD46 expression in CD46-costimulated T cells was downregulated by PGE 2 (Fig. 4B). These data show that, depending on the activa- tion signals, PGE 2 differentially affects a variety of phenotypic markers in T cells that are involved in regulating T cell activation as well as Treg functions. (Fig. ...
Citations
... The inhibitory effect of PGE2 on T lymphocytes has been shown in numerous studies [63][64][65]. The role of MSCs in inhibiting T cell activation and proliferation hasbeen demonstrated for the first time by Le Blanc et al. [66] and later confirmed many times [67][68][69]. ...
... The addition of PGE2 has been shown to strongly reduce the expression of CD46 in activated T cells. At the same time, CD46 activation correlated with EP4 receptor induction and a change in the profile of secreted cytokines [65]. An increase in Tregs proportion was noted following administration of IL-17A treated BM-MSCs to mice with ischemic reperfusion injury in the kidneys. ...
The ability of MSCs to modulate the inflammatory environment is well recognized, but understanding the molecular mechanisms responsible for these properties is still far from complete. Prostaglandin E2 (PGE2), a product of the cyclooxygenase 2 (COX-2) pathway, is indicated as one of the key mediators in the immunomodulatory effect of MSCs. Due to the pleiotropic effect of this molecule, determining its role in particular intercellular interactions and aspects of cell functioning is very difficult. In this article, the authors attempt to summarize the previous observations regarding the role of PGE2 and COX-2 in the immunomodulatory properties and other vital functions of MSCs. So far, the most consistent results relate to the inhibitory effect of MSC-derived PGE2 on the early maturation of dendritic cells, suppressive effect on the proliferation of activated lymphocytes, and stimulatory effect on the differentiation of macrophages into M2 phenotype. Additionally, COX-2/PGE2 plays an important role in maintaining the basic life functions of MSCs, such as the ability to proliferate, migrate and differentiate, and it also positively affects the formation of niches that are conducive to both hematopoiesis and carcinogenesis.
... Downregulation of cyclin D2 expression and upregulation of p27kip1 expression in T cells through TGF-β and HGF secreted by MSCs leads to cell cycle arrest in the G1 phase and inhibits T cell proliferation [77]. Downregulation of IL-2 receptor leads to inhibition of T cell proliferation through PGE2 secreted by MSCs and results in impairment of DNA binding activity through JAK-3 signaling inhibition [78]. Direct contact between MSC and T cell enhance immune-regulation of T cells. ...
Cellular therapy offers regeneration which curbs osteoarthritis of the knee. Among cellular therapies, mesenchymal stromal cells (MSCs) are readily isolated from various sources as culture expanded and unexpanded cellular population which are used as therapeutic products. Though MSCs possess a unique immunological and regulatory profile through cross-talk between MSCs and immunoregulatory cells (T cells, NK cells, dendritic cells, B cells, neutrophils, monocytes, and macrophages), they provide an immunotolerant environment when transplanted to the site of action. Immunophenotypic profile allows MSCs to escape immune surveillance and promotes their hypoimmunogenic or immune-privileged status. MSCs do not elicit a proliferative response when co-cultured with allogeneic T cells in vitro. MSCs secrete a wide range of anti-inflammatory mediators such as PGE-2, IDO, IL-1Ra, and IL-10. They also stimulate the resilient chondrogenic progenitors and enhance the chondrocyte differentiation by secretion of BMPs and TGFβ1. We highlight the various mechanisms of MSCs during tissue healing signals, their interaction with the immune system, and the impact of their lifespan in the management of osteoarthritis of the knee. A better understanding of the immunobiology of MSC renders them as an efficient therapeutic product for the management of osteoarthritis of the knee.
... 62 PGE2 has been shown to negatively regulate a variety of T-cell responses including altering the polarization of T-helper cells and enhancing the induction and differentiation of FOXP3 + CD4 + CD25+ regulatory T cells. 13,36,59,60 The ability of PGE2 to specifically suppress T-cell expansion/proliferation and activation has been demonstrated by others [62][63][64] and is dependent in large part on the EP2 receptor 63 as supported by our data (Figure 2). Specifically, PGE2 has been shown to suppress the activation and expansion of antigen specific T cells by inhibiting both IL-2 responsiveness and the production of IL-2, 62 65 This relative resistance to ligandinduced desensitization suggests that EP2 signaling may remain operative over prolonged periods of inflammation. ...
Graft-vs-host disease (GvHD) limits successful outcomes following allogeneic blood and marrow transplantation (allo-BMT). We examined whether the administration of human, bone marrow-derived, multipotent adult progenitor cells (MAPCs™) could regulate experimental GvHD. The immunoregulatory capacity of MAPC cells was evaluated in vivo using established murine GvHD models. Injection of MAPC cells on day +1 (D1) and +4 (D4) significantly reduced T-cell expansion and the numbers of donor-derived, Tumor Necrosis Factor Alpha (TNFα) and Interferon Gamma (IFNγ)-producing, CD4+ and CD8+ cells by D10 compared with untreated controls. These findings were associated with reductions in serum levels of TNFα and IFNγ, intestinal and hepatic inflammation and systemic GvHD as measured by survival and clinical score. Biodistribution studies showed that MAPC cells tracked from the lung and to the liver, spleen, and mesenteric nodes within 24 hours after injection. MAPC cells inhibited mouse T-cell proliferation in vitro and this effect was associated with reduced T-cell activation and inflammatory cytokine secretion and robust increases in the concentrations of Prostaglandin E2 (PGE2) and Transforming Growth Factor Beta (TGFβ). Indomethacin and E-prostanoid 2 (EP2) receptor antagonism both reversed while EP2 agonism restored MAPC cell-mediated in vitro T-cell suppression, confirming the role for PGE2. Furthermore, cyclo-oxygenase inhibition following allo-BMT abrogated the protective effects of MAPC cells. Importantly, MAPC cells had no effect on the generation cytotoxic T lymphocyte activity in vitro, and the administration of MAPC cells in the setting of leukemic challenge resulted in superior leukemia-free survival. Collectively, these data provide valuable information regarding the biodistribution and regulatory capacity of MAPC cells, which may inform future clinical trial design.
... Additionally, a reduction in the surface expression of CD80 and MHC class I molecules was found on CD14 + mononuclear phagocytes treated with PGE2 (Fig. 2). In line with our findings, the addition of PGE2 has been shown to reduce the expression of CD46 on activated T cells 42 . Furthermore, PGE2 also inhibits the expression of CD80, CD86 and MHC class I after LPS stimulation 43 . ...
Prostaglandin E2 (PGE2), an active lipid compound derived from arachidonic acid, regulates different stages of the immune response of the host during several pathologies such as chronic infections or cancer. In fact, manipulation of PGE2 levels was proposed as an approach for countering the Type I IFN signature of tuberculosis (TB). However, very limited information regarding the PGE2 pathway in patients with active TB is currently available. In the present work, we demonstrated that PGE2 exerts a potent immunosuppressive action during the immune response of the human host against Mycobacterium tuberculosis (Mtb) infection. Actually, we showed that PGE2 significantly reduced the surface expression of several immunological receptors, the lymphoproliferation and the production of proinflammatory cytokines. In addition, PGE2 promoted autophagy in monocytes and neutrophils cultured with Mtb antigens. These results suggest that PGE2 might be attenuating the excessive inflammatory immune response caused by Mtb, emerging as an attractive therapeutic target. Taken together, our findings contribute to the knowledge of the role of PGE2 in the human host resistance to Mtb and highlight the potential of this lipid mediator as a tool to improve anti-TB treatment.
... All together, these results demonstrate that PGE2 downregulates the expression of membrane receptors involved in T cell activation during stimulation with Mtb-Ag. In line with our ndings, the addition of PGE2 has been shown to reduce the expression of CD46 on activated T cells 30 . Furthermore, PGE2 also inhibits the expression of CD80, CD86 and MHC class I after LPS stimulation 31 . ...
Prostaglandin E2 (PGE2), an active lipid compound derived from arachidonic acid, regulates different stages of the immune response of the host during several pathologies such as chronic infections or cancer. In fact, manipulation of PGE2 levels was proposed as an approach for countering the Type I IFN signature of tuberculosis (TB). However, very limited information regarding the PGE2 pathway in patients with active TB is currently available. In the present work, we demonstrated that PGE2 exerts a potent immunosuppressive action during the immune response of the human host against Mycobacterium tuberculosis (Mtb) infection. Actually, we showed that PGE2 significantly reduced lymphoproliferation, the production of proinflammatory cytokines, and the surface expression of several immunological receptors. On the other hand, PGE2 promoted autophagy in monocytes and neutrophils cultured with Mtb antigens. These results suggest that PGE2 might be attenuating the excessive inflammatory immune response caused by Mtb , emerging as an attractive therapeutic target. Taken together, our findings contribute to the knowledge of the role of PGE2 in the human host resistance to Mtb and highlight the potential of this lipid mediator as a tool to improve anti-TB treatment.
... The induced expression of VCAM proteins in endothelial cells by cytokines stimulation allows lymphocytes (e.g., natural killer cells) adhesion to the endothelium and kills the affected cell [110], while iNOS produces abundantly pro-inflammatory nitric oxide, contributing to oxidative stress and cells toxicity by attracting neutrophils [111]. COX-2 is responsible for production of prostaglandins from arachidonic acid, which act as attractants for T cells [112], while the culmination of overexpression of cytokines stimulates T cells to differentiate into various functions, i.e., helper, killer or memory cells [113]. T cells and B cells are the part of adaptive immune system, not covered by this review (for the insights on the correlation between alcohol and the adaptive immune system, see [114]). ...
Ethanol misuse is frequently associated with a multitude of profound medical conditions, contributing to health-, individual-and social-related damage. A particularly dangerous threat from this classification is coined as alcoholic liver disease (ALD), a liver condition caused by prolonged alcohol overconsumption, involving several pathological stages induced by alcohol metabolic byproducts and sustained cellular intoxication. Molecular, pathological mechanisms of ALD principally root in the innate immunity system and are especially associated with enhanced functionality of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is an interesting and convoluted DNA transcription regulator, promoting both anti-inflammatory and pro-inflammatory gene expression. Thus, the abundancy of studies in recent years underlines the importance of NF-κB in inflammatory responses and the mechanistic stimulation of inner molecular motifs within the factor components. Hereby, in the following review, we would like to put emphasis on the correlation between the NF-κB inflammation signaling pathway and ALD progression. We will provide the reader with the current knowledge regarding the chronic and acute alcohol consumption patterns, the molecular mechanisms of ALD development, the involvement of the NF-κB pathway and its enzymatic regulators. Therefore, we review various experimental in vitro and in vivo studies regarding the research on ALD, including the recent active compound treatments and the genetic modification approach. Furthermore, our investigation covers a few human studies.
... These results demonstrate that PGE2 during stimulation with Mtb-Ag downregulates the expression of various membrane receptors involved in T cell activation. In this regard, the addition of PGE2 has been shown to reduce the expression of another costimulatory molecule, CD46 on activated T cells 26 . ...
Prostaglandin E2 (PGE2), an active lipid compound derived from arachidonic acid, regulates different stages of the immune response of the host during several pathologies such as chronic infections or cancer. Manipulation of PGE2 levels was proposed as an approach for countering the Type I IFN signature of tuberculosis (TB), but very limited information exists about this pathway in patients with active TB. Here, we demonstrated that PGE2 exerts a potent immunosuppressive action during the immune response of the human host against M. tuberculosis. Thus, we showed that PGE2 inhibited both lymphoproliferation and cytokine production of proinflammatory cytokines, together with a significant reduction of the surface expression of several immunological receptors in human cells. However, PGE2 promoted the autophagic flux of antigen-stimulated monocytes, even in the presence of IFNα. In this way, the attenuation of inflammation and immunopathology caused by an excessive immune response emerges as an attractive therapeutic target. Together, our findings contribute to the knowledge of Mtb-resistance mediated by PGE2 and highlight the potential of this lipid mediator as a tool to improve anti-TB treatment.
... For detection of IFNγ, IL-17, GM-CSF and IL-10 capture ELISAs were performed on day 5 supernatants, in duplicates. IL-10 and IFNγ secretion was determined by ELISA specific for human IL- 10 (BD Pharmingen, Oxford, UK) and IFNγ (Thermo-Fisher) as previously published 17,25 . ELISAs for IL- 17 and GMCSF were purchased from BioLegend (ELISA MAX Deluxe) and were performed according to the manufacturer's instructions. ...
Praziquantel (PZQ) is an anthelminthic human and veterinary drug used to treat trematode and cestode worms. Changes in immune responses have been demonstrated in humans following curative PZQ treatment of schistosome infections. These changes have been attributed to the removal of immunosupressive worms and immune responses to parasite antigens exposed from dying worms. To date, there has been no study investigating the potential direct effect of PZQ on the host immune cells. Herein, we analyzed the effect of PZQ on human CD4⁺ T cells classically costimulated by CD3/CD28 or costimulated by the complement regulator CD46 to induce Type 1 regulatory T cells (Tr1). Our results show that PZQ enhanced T cell proliferation, increased secretion of IL‐17 and IL‐10 but had no effect on secretion of GM‐CSF or IFNγ. Moreover, PZQ increased the co‐expression of CD49b and LAG‐3, a hallmark of Tr1 cells, suggesting increased Tr1 differentiation. Indeed, supernatants from PZQ‐treated cells were able to decrease bystander T cell activation, and this was partly reduced when blocking IL‐10. Hence, our study demonstrates that PZQ directly modulates human T cell activation and promotes Tr1 differentiation, suggesting that PZQ may have immunomodulatory functions in parasite‐unrelated human inflammatory diseases.
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... The contrasting effects of PGE 2 on T cell activation and cytokine production are in part due to differing expression of costimulatory molecules and the state of activation of T cells [50]. More importantly, the diverse and often contrasting actions of PGE 2 also stem from the heterogeneous cellular sources of PGE 2 and cell type-specific interaction with T effector cells. ...
Eicosanoids and specialized proresolving mediators (SPMs) regulate leukocyte function and inflammation. They are ideally positioned at the interface of the innate and adaptive immune responses when lymphocytes interact with leukocytes. Receptors for leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and SPMs are expressed on lymphocytes. Evidence points toward an essential role of these lipid mediators (LMs) in direct regulation of lymphocyte functions. SPMs, which include lipoxins, demonstrate comprehensive protective actions with lymphocytes. LTB4 and PGE2 regulation of lymphocytes is diverse and depends on the interaction of lymphocytes with other cells. Importantly, both LTB4 and PGE2 are essential regulators of T cell antitumor activity. These LMs are attractive therapeutic targets to control dysregulated innate and adaptive immune responses, promote lymphocyte antitumor activity, and prevent tumor immune evasion.
... In humans, PGE2 is the most abundant member of the prostanoid family, and most PGE2 is secreted by professional antigen-presenting cells (APCs) and stromal cells [21]. PGE2 is capable of mediating diverse effects depending on stimuli that are not well understood, but its role in suppression of T-cell activation and proliferation has been reported since 1971 [35], with newer studies also describing skewed differentiation [36] and induction of a suppressive phenotype in non-Treg CD4 + T cells, which were capable of suppressing the proliferation of other T cells undergoing activation [37]. Reported mechanisms include down-regulation of CD25, up-regulation of CD46, and altered responses to costimulation [36]. ...
... PGE2 is capable of mediating diverse effects depending on stimuli that are not well understood, but its role in suppression of T-cell activation and proliferation has been reported since 1971 [35], with newer studies also describing skewed differentiation [36] and induction of a suppressive phenotype in non-Treg CD4 + T cells, which were capable of suppressing the proliferation of other T cells undergoing activation [37]. Reported mechanisms include down-regulation of CD25, up-regulation of CD46, and altered responses to costimulation [36]. ...
The microenvironment of lymphoid organs can aid healthy immune function through provision of both structural and molecular support. In mice, fibroblastic reticular cells (FRCs) create an essential T-cell support structure within lymph nodes, while human FRCs are largely unstudied. Here, we show that FRCs create a regulatory checkpoint in human peripheral T-cell activation through 4 mechanisms simultaneously utilised. Human tonsil and lymph node–derived FRCs constrained the proliferation of both naïve and pre-activated T cells, skewing their differentiation away from a central memory T-cell phenotype. FRCs acted unilaterally without requiring T-cell feedback, imposing suppression via indoleamine-2,3-dioxygenase, adenosine 2A Receptor, prostaglandin E2, and transforming growth factor beta receptor (TGFβR). Each mechanistic pathway was druggable, and a cocktail of inhibitors, targeting all 4 mechanisms, entirely reversed the suppressive effect of FRCs. T cells were not permanently anergised by FRCs, and studies using chimeric antigen receptor (CAR) T cells showed that immunotherapeutic T cells retained effector functions in the presence of FRCs. Since mice were not suitable as a proof-of-concept model, we instead developed a novel human tissue–based in situ assay. Human T cells stimulated using standard methods within fresh tonsil slices did not proliferate except in the presence of inhibitors described above. Collectively, we define a 4-part molecular mechanism by which FRCs regulate the T-cell response to strongly activating events in secondary lymphoid organs while permitting activated and CAR T cells to utilise effector functions. Our results define 4 feasible strategies, used alone or in combinations, to boost primary T-cell responses to infection or cancer by pharmacologically targeting FRCs.
