Expression of genes controlling transport and catabolism of prostaglandin E<sub>2</sub>in lipopolysaccharide fever

Ivanov, Andrei I.; Scheck, Adrienne C.; Romanovsky, Andrej A.

doi:10.1152/ajpregu.00570.2002

Cited by 44 publications

(36 citation statements)

References 65 publications

(73 reference statements)

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“…Our results suggest that changes in PGT levels will affect both prostaglandin levels and estrogen synthesis in the local microenvironment, which could be important for normal menstrual function. Treatment with lipopolysaccharide (LPS) downregulates PGT in both the lung and the liver (46), which could lead to increased aromatase levels and estrogen synthesis. This possibility should be explored, as estrogen antagonizes some of the proinflammatory effects of LPS (47).…”

Section: A B C D E F G H Discussionmentioning

confidence: 99%

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

Subbaramaiah

Hudis

Dannenberg

2011

Cancer Prevention Research

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Cytochrome P450 aromatase, encoded by the CYP19 gene, catalyzes estrogen synthesis. In obese postmenopausal women, increased estrogen synthesis in adipose tissue has been linked to hormonedependent breast carcinogenesis. Hence, it is important to elucidate the mechanisms that regulate CYP19 gene expression. Prostaglandin E 2 (PGE 2 ) stimulates the cyclic AMP (cAMP) ! protein kinase A (PKA) ! cAMP responsive element binding protein (CREB) pathway leading to increased CYP19 transcription. The prostaglandin transporter (PGT) removes PGE 2 from the extracellular milieu and delivers it to the cytosol, where it is inactivated. The main objective of this study was to determine whether PGT regulates CYP19 transcription. Silencing of PGT in preadipocytes increased PGE 2 levels in the extracellular medium, thereby stimulating the cAMP ! PKA pathway resulting in enhanced interaction between pCREB, p300, and the CYP19 I.3/II promoter. A reciprocal decrease in the interaction between the CYP19 I.3/II promoter and BRCA1, a repressor of CYP19 transcription, was observed. Overexpressing PGT reduced extracellular PGE 2 levels, suppressed the cAMP ! PKA pathway, enhanced the interaction between BRCA1 and p300, and inhibited aromatase expression. We also compared the PGT ! aromatase axis in preadipocytes versus adipocytes. Aromatase levels were markedly increased in preadipocytes versus adipocytes. This increase in aromatase was explained, at least in part, by reduced PGT levels leading to enhanced PGE 2 ! cAMP ! PKA signaling. In addition to regulating aromatase expression, PGT-mediated changes in extracellular PGE 2 levels were a determinant of adipocyte differentiation. Collectively, these results suggest that PGT modulates adipogenesis and thereby PGE 2 -mediated activation of the cAMP ! PKA ! CREB pathway leading to altered CYP19 transcription and aromatase activity.

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Section: A B C D E F G H Discussionmentioning

confidence: 99%

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

Subbaramaiah

Hudis

Dannenberg

2011

Cancer Prevention Research

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“…PGE 2 is synthesized from arachidonic acid primarily via the actions of COX-2. It is known that .90% of circulating PGE 2 is rapidly catabolized to inactive forms on the first pass in the lungs (49,50,57). Therefore, studies have used the measurement of PGEM as a common alternative to indicate the levels of PGE 2 (51-53, 58, 59).…”

Section: Discussionmentioning

confidence: 99%

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

Sio

Ang

et al. 2010

The Journal of Immunology

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Acute lung injury (ALI) is a major cause of mortality in burn patients, even without direct inhalational injury. Identification of early mediators that instigate ALI after burn and of the molecular mechanisms by which they work are of high importance but remain poorly understood. We previously reported that an endogenous neuropeptide, substance P (SP), via binding neurokinin-1 receptor (NK1R), heightens remote ALI early after severe local burn. In this study, we examined the downstream signaling pathway following SP-NK1R coupling that leads to remote ALI after burn. A 30% total body surface area full-thickness burn was induced in male BALB/c wild-type (WT) mice, preprotachykinin-A (PPT-A) gene-deficient mice, which encode for SP, and PPT-A−/− mice challenged with exogenous SP. Local burn injury induced excessive SP-NK1R signaling, which activated ERK1/2 and NF-κB, leading to significant upregulation of cyclooxygenase (COX)-2, PGE metabolite, and remote ALI. Notably, lung COX-2 levels were abrogated in burn-injured WT mice by L703606, PD98059, and Bay 11-7082, which are specific NK1R, MEK-1, and NF-κB antagonists, respectively. Additionally, burn-injured PPT-A−/− mice showed suppressed lung COX-2 levels, whereas PPT-A−/− mice injected with SP showed augmented COX-2 levels postburn, and administration of PD98059 and Bay 11-7082 to burn-injured PPT-A−/− mice injected with SP abolished the COX-2 levels. Furthermore, treatment with parecoxib, a selective COX-2 inhibitor, attenuated proinflammatory cytokines, chemokines, and ALI in burn-injured WT mice and PPT-A−/− mice injected with SP. To our knowledge, we show for the first time that SP-NK1R signaling markedly elevates COX-2 activity via ERK1/2 and NF-κB, leading to remote ALI after burn.

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“…, where N is the threshold cycle number, i.e., the number of the amplification cycle in which fluorescence of a given sample becomes significantly different from the baseline signal (36). The indexes i and h refer to the gene of interest and housekeeping gene, respectively; the index t refers to individual samples from rats treated with either LPS or saline; and the index c refers to control samples (namely, samples pooled from untreated rats).…”

Section: Functional Activity Of the Cox-1 Pathway And Cox-1 Expressionmentioning

confidence: 99%

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

Steiner

Hunter²,

Phipps³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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DL, Romanovsky AA. Cyclooxygenase-1 or -2-which one mediates lipopolysaccharide-induced hypothermia? Am J Physiol Regul Integr Comp Physiol 297: R485-R494, 2009. First published June 10, 2009 doi:10.1152/ajpregu.91026.2008.-Systemic inflammation is associated with either fever or hypothermia. Fever, a response to mild systemic inflammation, is mediated by cyclooxygenase (COX)-2 and not by COX-1. However, it is still disputed whether COX-2, COX-1, neither, or both mediate(s) responses to severe systemic inflammation, and, in particular, the hypothermic response. We compared the effects of SC-236 (COX-2 inhibitor) and SC-560 (COX-1 inhibitor) on the deep body temperature (Tb) of rats injected with a lower (10 g/kg iv) or higher (1,000 g/kg iv) dose of LPS at different ambient temperatures (Tas). At a neutral Ta (30°C), the rats responded to LPS with a polyphasic fever (lower dose) or a brief hypothermia followed by fever (higher dose). SC-236 (2.5 mg/kg iv) blocked the fever induced by either LPS dose, whereas SC-560 (5 mg/kg iv) altered neither the febrile response to the lower LPS dose nor the fever component of the response to the higher dose. However, SC-560 blocked the initial hypothermia caused by the higher LPS dose. At a subneutral T a (22°C), the rats responded to LPS with early (70 -90 min, nadir) dose-dependent hypothermia. The hypothermic response to either dose was enhanced by SC-236 but blocked by SC-560. The hypothermic response to the higher LPS dose was associated with a fall in arterial blood pressure. This hypotensive response was attenuated by either SC-236 or SC-560. At the onset of LPS-induced hypothermia and hypotension, the functional activity of the COX-1 pathway (COX-1-mediated PGE2 synthesis ex vivo) increased in the spleen but not liver, lung, kidney, or brain. The expression of splenic COX-1 was unaffected by LPS. We conclude that COX-1, but not COX-2, mediates LPS hypothermia, and that both COX isoforms are required for LPS hypotension. body temperature; thermoregulation; fever; inflammation SO STRONGLY IS SYSTEMIC INFLAMMATION associated with changes in deep body temperature (T b ) that every clinical definition of the systemic inflammatory response syndrome includes a change in T b (11,48). Whereas the majority (ϳ90%) of patients with systemic inflammation have an increased T b , a number of them (ϳ10%) have a lowered T b (6, 17). Thermoregulatory manifestations are also present in animal models of systemic inflammation. In a rat model of systemic inflammation induced by bacterial LPS, the pattern of T b change depends on the ambient temperature (T a ) and the LPS dose. At a neutral or supraneutral T a (warm environment), fever is the prevailing response; the fever is monophasic when the dose of LPS is low (just suprathreshold), but it turns polyphasic as the dose increases (66, 68, 69, 71, 79); a mild hypothermia may precede the polyphasic fever when the dose of LPS is high (68). At a subneutral T a (cool environment), hypothermia followed by fever is the predominant response; th...

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Expression of genes controlling transport and catabolism of prostaglandin E₂in lipopolysaccharide fever

Cited by 44 publications

References 65 publications

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

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Expression of genes controlling transport and catabolism of prostaglandin E2in lipopolysaccharide fever

Cited by 44 publications

References 65 publications

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

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Expression of genes controlling transport and catabolism of prostaglandin E₂in lipopolysaccharide fever