Lipopolysaccharide-Dependent Prostaglandin E2 Production Is Regulated by the Glutathione-Dependent Prostaglandin E2 Synthase Gene Induced by the Toll-Like Receptor 4/MyD88/NF-IL6 Pathway

Uematsu, Satoshi; Matsumoto, Makoto; Takeda, Kiyoshi; Akira, Shizuo

doi:10.4049/jimmunol.168.11.5811

Cited by 282 publications

(247 citation statements)

References 33 publications

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“…Although these effects of PGE 2 on the immune system have been known for several years, the role of PGE 2 during infections is just starting to be examined. Recent studies show that bacterial components LPS, CpG DNA, and peptidoglycan wall can all induce COX-2 expression and PGE 2 production (21,22,25). Interestingly, L. pneumophila and Escherichia coli both use PGE 2 to modulate T cell function (31,63).…”

Section: Discussionmentioning

confidence: 99%

“…Although the effects of PG on the immune system are understood, their role in infectious disease is not. Recent studies have clearly demonstrated that the bacterial products LPS, peptidoglycan, and CpG DNA can initiate COX gene up-regulation and PG secretion (21)(22)(23)(24)(25). Thus, bacterial infections that can induce PGE 2 are able to inhibit T cell function, and should gain an advantage in in vivo growth.…”

mentioning

confidence: 99%

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Francisella tularensis-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response

Woolard

Wilson

Hensley

et al. 2007

The Journal of Immunology

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Francisella tularensis is a highly infectious bacterial pathogen, and is likely to have evolved strategies to evade and subvert the host immune response. In this study, we show that F. tularensis infection of macrophages alters T cell responses in vitro, by blocking T cell proliferation and promoting a Th2-like response. We demonstrate that a soluble mediator is responsible for this effect and identify it as PGE2. Supernatants from F. tularensis-infected macrophages inhibited IL-2 secretion from both MHC class I and MHC class II-restricted T cell hybridomas, as well as enhanced a Th2-like response by inducing increased production of IL-5. Furthermore, the soluble mediator blocked proliferation of naive MHC class I-restricted T cells when stimulated with cognate tetramer. Indomethacin treatment partially restored T cell proliferation and lowered IL-5 production to wild-type levels. Macrophages produced PGE2 when infected with F. tularensis, and treatment of infected macrophages with indomethacin, a cyclooxygenase-1/cyclooxygenase-2 inhibitor, blocked PGE2 production. To further demonstrate that PGE2 was responsible for skewing of T cell responses, we infected macrophages from membrane PGE synthase 1 knockout mice (mPGES1−/−) that cannot produce PGE2. Supernatants from F. tularensis-infected membrane PGE synthase 1−/− macrophages did not inhibit T cell proliferation. Furthermore, treatment of T cells with PGE2 recreated the effects seen with infected supernatant. From these data, we conclude that F. tularensis can alter host T cell responses by causing macrophages to produce PGE2. This study defines a previously unknown mechanism used by F. tularensis to modulate adaptive immunity.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Francisella tularensis-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response

Woolard

Wilson

Hensley

et al. 2007

The Journal of Immunology

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“…The temporal and spatial properties of PGE 2 synthesis are determined by the regulated expression of each of the enzymes involved in this cascade. Of the several putative PGES that have been described, mPGES1 is the best characterized, and a role for mPGES1 in inflammation and febrile responses has been clearly demonstrated (21,32,33). Although mPGES1 is expressed in the kidney (17)(18)(19)34), its contribution to PGE 2 synthesis in the kidney and to the consequent regulation renal functions has not been characterized previously.…”

Section: Discussionmentioning

confidence: 99%

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

François

Facemire

Kumar

et al. 2007

Journal of the American Society of Nephrology

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Prostaglandin E 2 (PGE 2 ) is one of the most ubiquitous prostanoids in the kidney, where it may influence a wide range of physiologic functions. PGE 2 is generated through enzymatic metabolism of prostanoid endoperoxides by specific PGE synthases (PGES). Several putative PGES have been identified and cloned, including the membrane-associated, inducible microsomal PGES1 (mPGES1), which is expressed in the kidney. To evaluate the physiologic role of mPGES1 in the kidney, mice with targeted disruption of mPges1 gene were studied, with a focus on responses where PGE 2 has been implicated, including urinary concentration, regulation of blood pressure, and response to a loop diuretic. The absence of mPGES1 was associated with a 50% decrease in basal excretion of PGE 2 in urine (P < 0.001). In female but not male mPGES1-deficient mice, there was a reciprocal increase in basal excretion of other prostanoids. Nonetheless, urinary osmolalities were similar in mPges1 ؉/؉ and mPges1 ؊/؊ mice at baseline and after 12 h of water deprivation. Likewise, there were no differences in blood pressure between mPGES1-deficient and wild-type mice on control or high-or low-salt diets. The furosemide-induced increase in urinary PGE 2 excretion that was seen in wild-type mice was attenuated in mPGES1-deficient mice. However, furosemide-associated diuresis was reduced only in male, not female, mPGES1-deficient mice. Stimulation of renin by furosemide was not affected by mPGES1 deficiency. These data suggest that mPGES1 contributes to basal synthesis of PGE 2 , but there are other pathways that lead to renal PGE 2 synthesis. Moreover, there are significant gender differences in physiologic contributions of mPGES1 to control kidney function.

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“…One of the nuclear targets in the TLR-mediated signaling pathway is NF-IL6, a member of the C/EBP family of transcription factors (Tanaka et al, 1995). NF-IL6 was originally identified as a transcription factor that specifically binds to an IL-1 responsive element in the IL-6 gene promoter (Akira et al, 1990), and was subsequently shown to play an important role in LPS-induced gene expression in macrophages (Gorgoni et al, 2001;Uematsu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

Chan

Chen

et al. 2006

Oncogene

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Paclitaxel (Taxol) is an antineoplastic agent that specifically targets microtubules and arrests cells at the G2/M phase of the cell cycle. In addition to mitotic arrest, the activation of c-Jun N-terminal kinase (JNK) signaling pathway has been demonstrated to be involved in the process leading to apoptosis. In an attempt to explore what genes are transcriptionally regulated by the activated JNK signaling pathway upon paclitaxel treatment, we used cDNA microarrays to analyse the changes of gene expression in human ovarian cancer cells that were treated with paclitaxel and/or the JNK inhibitor SP600125. Among 20 genes that were specifically regulated by the paclitaxel-activated JNK pathway, interleukin (IL)-6 was shown to elicit function through the JAK-STAT signaling pathway in an autocrine and/or paracrine fashion. Subsequently, we identified that 87.5% of eight tested ovarian cancer lines secreted detectable levels of IL-6, which could be further upregulated 2-3.2 fold by 1 lM paclitaxel. Dissection on regulatory pathways for IL-6 indicated that (i) when ovarian cancer cells were treated with paclitaxel at low but clinically achievable concentrations (exemplified by 1 lM in this study), the JNK signaling pathway was the major stimulator of IL-6 gene regulation and (ii) at suprapharmacologically high concentrations (exemplified by 50 lM), paclitaxel exerted lipopolysaccharide-like effects, most likely through the Toll-like receptor 4 signaling pathway. Collectively, these results suggest that paclitaxel upregulates functional IL-6 expression in human ovarian cancer cells through multiple signaling pathways.

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Lipopolysaccharide-Dependent Prostaglandin E2 Production Is Regulated by the Glutathione-Dependent Prostaglandin E2 Synthase Gene Induced by the Toll-Like Receptor 4/MyD88/NF-IL6 Pathway

Cited by 282 publications

References 33 publications

Francisella tularensis-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response

Francisella tularensis-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

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