Prostaglandin E2 induces apoptosis in immature normal and malignant B lymphocytes

Brown, Deborah M.; Warner, Garvin L.; Alés-Martínez, JoséE.; Scott, David W.; Phipps, Richard P.

doi:10.1016/0090-1229(92)90226-e

Cited by 80 publications

(43 citation statements)

References 33 publications

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“…[18][19][20][21] Interestingly, one of the mechanisms described to mediate PGE 2 -mediated apoptosis is the upregulation of CD95L. 22 However, in agreement with our results, data in the literature also point out to a protective effect of PGE 2 .…”

Section: Discussionsupporting

confidence: 52%

TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

et al. 2008

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Antigen-presenting cells (APCs) control T-cell responses by multiple mechanisms, including the expression of co-stimulatory molecules and the production of cytokines and other mediators that control T-cell proliferation, survival and differentiation. Here, we demonstrate that soluble factor(s) produced by Toll-like receptor (TLR)-activated APCs suppress activation-induced cell death (AICD). This effect was observed in non-stimulated APCs, but it was significantly increased after lipopolysaccharide (LPS) treatment. Using different KO mice, we found that the LPS-induced protective factor is dependent on TLR4/MyD88. We identified the protective factor as prostaglandin E 2 (PGE 2 ) and showed that both APC-derived supernatants and PGE 2 prevented CD95L upregulation in T cells in response to TCR/CD3 stimulation, thereby avoiding both AICD and activated T cell killing of target macrophages. The PGE 2 receptors, EP2 and EP4, appear to be involved since pharmacological stimulation of these receptors mimics the protective effect on T cells and their respective antagonists interfere with the protection induced by either APCs derived or synthetic PGE 2 . Finally, the engagement of EP2 and EP4 synergistically activates protein kinase A (PKA) and exchange protein directly activated by cAMP pathways to prevent AICD. Taken together, these results indicate that APCs can regulate T-cell levels of CD95L by releasing PGE 2 in response to LPS through a TLR4/MyD88-dependent pathway, with consequences for both T cell and their own survival. Cell Death and Differentiation (2008) 15, 1901-1909 doi:10.1038/cdd.2008 ; published online 26 September 2008Proper activation of T cells is imperative to achieve an efficient immunity against pathogens and tumors and, at the same time, to avoid undesirable collateral effects, such as the appearance of autoimmune diseases. Secondary lymphoid organs provide a particular microenvironment specialized in assembling all the cohorts necessary to perform such a remarkable task. 1 In the presence of antigens, antigenpresenting cells (APCs) and their soluble products, including a variety of cytokines, lipid mediators and chemokines, T cells are activated through the engagement of their T-cell receptors (TCR) and co-stimulatory molecules. As a result, T cells can proliferate, differentiate to effector or memory cells, or eventually die.Deletion of autoreactive T cells is one of the key mechanisms involved in the process of peripheral tolerance that helps to prevent the appearance of autoimmune diseases. 2 Similarly, elimination of chronically stimulated T cells that can potentially be harmful to the host by the means of the production of abnormal levels of inflammatory cytokines is another feature of an efficient immune system. Finally, death of effector T cells at the end of an immune response is a very important homeostatic mechanism designed to shrink an enlarged, no longer necessary cell population that can compete for growth and survival factors with newly activated antigen-specific T-cell clones. In a...

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Section: Discussionsupporting

confidence: 52%

TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

et al. 2008

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“…Furthermore, PGE2 has recently been implicated in the growth and differentiation of human B-lymphocytes activated through their CD40 antigen (Garrone et al, 1994). In spite of the evidence that PGE2 can act as a growth regulator, other data have demonstrated that high levels of PGE2 can cause growth arrest and, potentially, programmed cell death in a number of primary and established cell lines of immunological origins, such as thymocytes (Suzuki et al, 1991) and B-lymphocytes (Brown et al, 1992). We, however, did not find any evidence that dmPGE2, at the concentrations used in this paper (as described in Materials and methods), promotes cell death in PC-3 cells.…”

Section: Discussionmentioning

confidence: 99%

Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells

Dahiya²,

1997

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Summary Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclooxygenases: COX-1 (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E2 (dmPGE2) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE2 to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE2 concentration. DmPGE2 also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE2 regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE2 concentration, with maximum stimulation seen at 5 [sg ml-'. The non-steroidal anti-inflammatory drug flurbiprofen (5 FM), in the presence of exogenous dmPGE2, inhibited the up-regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE2 has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE2, perhaps resulting from changes in local cellular PGE2 concentrations.

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“…PGE2 can induce apoptosis in mononuclear cells in vitro as well as in vivo under various conditions [8,9,27,28], although it has also been reported to suppress activation-induced apoptosis [10]. In murine B-cell lines, a dose-dependent growth inhibition of immature cells was reported, whereas mature cell lines were less susceptible [20].…”

Section: 3 Functional Pge2 Receptors Of the Ep4 Subtype On Human Mmentioning

confidence: 99%

“…Furthermore, PGE2 supports the class switch from IgM to IgE in B-lymphocytes [6,7]. Finally, it can modulate agonist-induced apoptosis in T-and B-lymphocytes [8][9][10]. It is as yet unknown by which type of PGE2 receptor these effects are mediated.…”

Section: Introductionmentioning

confidence: 99%

Exclusive expression of the Gs‐linked prostaglandin E₂ receptor subtype 4 mRNA in human mononuclear Jurkat and KM‐3 cells and coexpression of subtype 4 and 2 mRNA in U‐937 cells

1996

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Prostaglandin E2 induces apoptosis in immature normal and malignant B lymphocytes

Cited by 80 publications

References 33 publications

TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells

Exclusive expression of the Gs‐linked prostaglandin E₂ receptor subtype 4 mRNA in human mononuclear Jurkat and KM‐3 cells and coexpression of subtype 4 and 2 mRNA in U‐937 cells

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Prostaglandin E2 induces apoptosis in immature normal and malignant B lymphocytes

Cited by 80 publications

References 33 publications

TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells

Exclusive expression of the Gs‐linked prostaglandin E2 receptor subtype 4 mRNA in human mononuclear Jurkat and KM‐3 cells and coexpression of subtype 4 and 2 mRNA in U‐937 cells

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Exclusive expression of the Gs‐linked prostaglandin E₂ receptor subtype 4 mRNA in human mononuclear Jurkat and KM‐3 cells and coexpression of subtype 4 and 2 mRNA in U‐937 cells