Roles of Cyclooxygenase (COX)-1 and COX-2 in Prostanoid Production by Human Endothelial Cells: Selective Up-Regulation of Prostacyclin Synthesis by COX-2

Caughey, Gillian E.; Cleland, Leslie G.; Penglis, Peter S.; Gamble, Jennifer R.; James, Michael J.

doi:10.4049/jimmunol.167.5.2831

Cited by 247 publications

(196 citation statements)

References 36 publications

(40 reference statements)

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“…Moreover, we confirmed the colocalization of COX-2 þ tumor cells and COX-2 þ infiltrating CD14 þ monocytes by evaluating the immunohistochemistry (IHC) staining on paraffin-embedded tumor tissues from patients with stage III melanoma (data not shown). However, blockade of COX-2 activity in the patient-derived monocytes did not yield consistent T-cell rescue, which suggests that PGE 2 from patient MDSCs are synthesized via an alternative pathway, that is, COX-1 activity (44). Strikingly, we found that treatment of melanoma patientderived monocytes with PGE 2 provided them with capacity to induce complete abrogation of T-cell proliferation and IFNg production.…”

Section: May Involve Blocking the Negative Influence Of Mdscs On T Cementioning

confidence: 69%

Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms

et al. 2013

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Tumors can suppress the host immune system by employing a variety of cellular immune modulators, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). In the peripheral blood of patients with advanced stage melanoma, there is an accumulation of CD14 þ HLA-DR lo/À MDSC that suppress autologous T cells ex vivo in a STAT-3-dependent manner. However, a precise mechanistic basis underlying this effect is unclear, particularly with regard to whether the MDSC induction mechanism relies on cell-cell contact of melanoma cells with CD14 þ cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14 þ monocytes, leading them to resemble MDSCs characterized in patients with advanced stage melanoma. These MDSC-like cells potently suppress autologous T-cell proliferation and IFN-g production. Notably, induction of myeloid-suppressive functions requires contact or close proximity between monocytes and tumor cells. Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14 þ cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE 2 ), STAT-3, and superoxide. Indeed, PGE 2 was sufficient to confer to monocytes the ability to suppress proliferation and IFN-g production by autologous T cells ex vivo. In summary, our results reveal how immune suppression by MDSC can be initiated in the tumor microenvironment of human melanoma. Cancer Res; 73(13); 3877-87. Ó2013 AACR.

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Section: May Involve Blocking the Negative Influence Of Mdscs On T Cementioning

confidence: 69%

Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms

et al. 2013

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“…These findings confirm that both isoforms of COX are present, functional, and involved in relaxation responses to AA. The expression of COX-2 in normal mesenteric arteries was unexpected, given that this isoform is predominantly expressed in disease states such as inflammation and atherosclerosis (1,6,10,31). However, a previous study (12) has reported that both COX-1 and -2 are constitutively expressed in the rat lung vasculature and that COX-2 plays a predominant role in prostanoid-related regulation of pulmonary vascular tone.…”

Section: Discussionmentioning

confidence: 90%

Cyclooxygenase- and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries

Zhang¹,

Gauthier²,

Chawengsub³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Cyclooxygenase-and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries. Am J Physiol Heart Circ Physiol 288: H302-H309, 2005. First published September 23, 2004; doi:10.1152/ ajpheart.00661.2004We recently reported that the lipoxygenase product 11,12,15-trihydroxyeicosatrienoic acid (THETA) mediates arachidonic acid (AA)-induced relaxation in the rabbit aorta. This study was designed to determine whether this lipoxygenase metabolite is involved in relaxation responses to AA in rabbit small mesenteric arteries. AA (10 Ϫ9 -10 Ϫ4 M) produced potent relaxations in isolated phenylephrine-preconstricted arteries, with a maximal relaxation of 99 Ϯ 0.5% and EC50 of 50 nM. The cyclooxygenase (COX) inhibitors indomethacin (10 M), NS-398 (10 M, selective for COX-2), and SC-560 (100 nM, selective for COX-1) caused a marked rightward shift of concentration responses to AA. With the use of immunohistochemical analysis, both COX-1 and COX-2 were detected in endothelium and smooth muscle of small mesenteric arteries. Indomethacin-resistant relaxations were further reduced by the lipoxygenase inhibitors cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC; 1 M), nordihydroguaiaretic acid (NDGA; 1 M), and ebselen (1 M). HPLC analysis showed that [ 14 C]AA was metabolized by mesenteric arteries to PGI2, PGE2, THETAs, hydroxyepoxyeicosatrienoic acids (HEETAs), and 15-hydroxyeicosatetraenoic acid (15-HETE). The production of PGI2 and PGE2 was blocked by indomethacin, and the production of THETAs, HEETAs, and 15-HETE was inhibited by CDC and NDGA. Column fractions corresponding to THETAs were further purified, analyzed by gas chromatography/mass spectrometry, and identified as 11,12,15-and 11,14,15-THETA. PGI2, PGE2, and purified THETA fractions relaxed mesenteric arteries precontracted with phenylephrine. The AA-and THETA-induced relaxations were blocked by high K ϩ (60 mM). These findings provide functional and biochemical evidence that AA-induced relaxation in rabbit small mesenteric arteries is mediated through both COX and lipoxygenase pathways.endothelium-derived factors; trihydroxyeicosatrienoic acid; prostaglandin E2; prostaglandin I2; endothelium-derived hyperpolarizing factor ACETYLCHOLINE, BRADYKININ, AND OTHER VASODILATORS elicit endothelium-dependent relaxation by release of a number of soluble factors from the vascular endothelium (8,17,22,23). These relaxing factors include nitric oxide (NO), prostacyclin, and a group of compounds termed EDHFs. Although the chemical identity of EDHF remains controversial, its action has been demonstrated in a number of vascular beds, where a significant portion of endothelium-dependent relaxation persists in the presence of NO synthase (NOS) and cyclooxygenase (COX) inhibitors such as N-nitro-L-arginine (L-NNA) and indomethacin. This endothelium-dependent, non-NO, and nonprostacyclin relaxation is associated with smooth muscle hyperpolarization and is sensitive to K ϩ channel blockers such as apamin and charybdotoxin (7,9,14,16,24). The mediators of EDHF ...

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“…Although not specifically tested in these studies, it is likely that PGI 2 exerts its effects primarily by acutely decreasing the secretion of ghrelin from these enteric cells. IL-1b has been previously shown to increase the production of PGI 2 in numerous other tissues, primarily by upregulating the expression and action of COX-2 (Belt et al 1999, Caughey et al 2001, Walch and Morris 2002, Itoh et al 2003. Obviously, one of the outcomes of this acute decrease in circulating ghrelin would be the development of anorexia as is typical of the acute illness response.…”

Section: Discussionmentioning

confidence: 99%

Prostacyclin signaling regulates circulating ghrelin during acute inflammation

Madison

Scarlett

Levasseur

et al. 2007

Journal of Endocrinology

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Ghrelin is an octanoylated 28 amino acid peptide predominantly secreted by the stomach, and has potent stimulatory effects on appetite. Several laboratories, including our own, have demonstrated that ghrelin levels fall in states of acute inflammation brought about by injection of bacterial lipopolysaccharide (LPS). We now demonstrate that the decrease in circulating ghrelin is not due to a decrease in ghrelin gene expression, but is instead likely to be due to an acute decrease in ghrelin secretion. Furthermore, we have found that the change in circulating ghrelin during acute inflammation required a prostaglandin second messenger, but did not require the synthesis of nitric oxide. Interestingly, i.v. injection of prostaglandin E 2 failed to decrease circulating ghrelin levels, whereas prostacyclin decreased circulating ghrelin to a similar extent as did LPS. We also provide anatomical evidence for the mechanism of the regulation of ghrelin by inflammation. We demonstrate that the type 1 interleukin-1b (IL-1b) receptor is expressed within the gastric mucosa, but is not expressed by ghrelin cells. The prostacyclin receptor was also expressed in the gastric mucosa, and the majority of ghrelin-producing cells were found to co-express this receptor. Mice with genetic deletion of the type 1 IL-1 receptor do not suppress circulating ghrelin levels with LPS administration. Collectively, these data support a model in which the mechanism of inflammation induced decreases in ghrelin are due to the action of IL-1b on cells within the gastric mucosa that in turn produce prostacyclin as a second messenger. These data provide further support for the potential role of ghrelin as a therapeutic agent in acute and chronic inflammatory diseases.

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Roles of Cyclooxygenase (COX)-1 and COX-2 in Prostanoid Production by Human Endothelial Cells: Selective Up-Regulation of Prostacyclin Synthesis by COX-2

Cited by 247 publications

References 36 publications

Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms

Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms

Cyclooxygenase- and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries

Prostacyclin signaling regulates circulating ghrelin during acute inflammation

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