Phosphatidylinositol 3-Kinase Activity Negatively Regulates Stability of Cyclooxygenase 2 mRNA

Monick, Martha M.; Robeff, Pamela K.; Butler, Noah S.; Flaherty, Dawn M.; Carter, A. Brent; Peterson, Michael W.; Hunninghake, Gary W.

doi:10.1074/jbc.m203218200

Cited by 86 publications

(66 citation statements)

References 60 publications

(68 reference statements)

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“…Using actinomycin D to block transcription we have found a stability of COX-2 mRNA in PMN above that reported for human monocytes [49] and alveolar macrophages [50]. Moreover, studies in these cells required preincubation with LPS for periods of 4 to 24 h to allow induction of COX-2 mRNA, whereas in the present study the preincubation period could be suppressed due to the presence of preformed COX-2 mRNA.…”

Section: Discussionsupporting

confidence: 46%

“…Interestingly, a recent report using a preparation of platelets and monocytes has shown that efficient induction of COX-2 protein requires combination of signals involving activation of jB-driven transcriptional activation and stabilization of COX-2 mRNA by silencing the AU-rich mRNA element [51]. Whereas cells with a lasting life span might need combination of mechanisms for a timely regulation of COX-2 protein expression, the existence of rapid regulatory mechanisms in short-lived cells such as PMN seems most appropriate.Using actinomycin D to block transcription we have found a stability of COX-2 mRNA in PMN above that reported for human monocytes [49] and alveolar macrophages [50]. Moreover, studies in these cells required preincubation with LPS for periods of 4 to 24 h to allow induction of COX-2 mRNA, whereas in the present study the preincubation period could be suppressed due to the presence of preformed COX-2 mRNA.…”

supporting

confidence: 46%

“…Regulation of COX-2 protein by the 3 0 -UTR has been described at least in monocytes, macrophages, and neoplastic cells since COX-2 mRNA contains 23 copies of the AUUUA RNA instability element, which makes this mRNA short-lived and suitable for post-transcriptional regulation by mechanisms dependent on at least the p38-MAP kinase [49] and the PI3K routes [50]. Interestingly, a recent report using a preparation of platelets and monocytes has shown that efficient induction of COX-2 protein requires combination of signals involving activation of jB-driven transcriptional activation and stabilization of COX-2 mRNA by silencing the AU-rich mRNA element [51].…”

Section: Discussionmentioning

confidence: 99%

“…Whereas the secondary structure energy of the 5 0 -UTR of COX-2 is more consistent with transcriptional control, the presence of polypyrimidine tracts and/or as yet unidentified binding proteins may make COX-2 mRNA responsive to translational control via 5 0 -UTR in PMN. In addition, the detection of COX-2 mRNA in resting PMN, but not the protein, the effect of rapamycin at the concentrations tested [45][46][47][48], and the phosphorylation of 4E-BP1, which allows eIF4E to recognize the 7-methyl cap of mRNA and the initiation of translation, support post-transcriptional regulation.Regulation of COX-2 protein by the 3 0 -UTR has been described at least in monocytes, macrophages, and neoplastic cells since COX-2 mRNA contains 23 copies of the AUUUA RNA instability element, which makes this mRNA short-lived and suitable for post-transcriptional regulation by mechanisms dependent on at least the p38-MAP kinase [49] and the PI3K routes [50]. Interestingly, a recent report using a preparation of platelets and monocytes has shown that efficient induction of COX-2 protein requires combination of signals involving activation of jB-driven transcriptional activation and stabilization of COX-2 mRNA by silencing the AU-rich mRNA element [51].…”

mentioning

confidence: 99%

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Mannan and peptidoglycan induce COX‐2 protein in human PMN via the mammalian target of rapamycin

et al. 2007

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The induction of cyclooxygenase-2 (COX-2) protein expression was assessed in human polymorphonuclear leukocytes (PMN) stimulated via receptors of the innate immune system. Peptidoglycan (PGN) and mannan, and at a lower extent the bacterial lipoprotein mimic palmitoyl-3-cysteine-serine-lysine-4, induced COX-2 protein expression. In contrast, lipoteichoic acid and muramyldipeptide were irrelevant stimuli. The mRNA encoding COX-2 was present in resting PMN at an extent quite similar to that detected in stimulated PMN, whereas the expression of COX-2 protein was undetectable. Treatment with the phosphatidylinositol 3-kinase inhibitor (PI3K) wortmaninn, the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and the translation inhibitor cycloheximide blocked the induction of COX-2 protein in response to mannan and PGN, whereas the transcriptional inhibitor actinomycin D did not show a significant effect. These results disclose a capability of pathogen-associated molecular patterns to induce the oxidative metabolism of arachidonic acid more robust than that of PMN archetypal chemoattractants, since mannan and PGN make it coincidental the release of arachidonic acid with a rapid induction of COX-2 protein regulated by a signaling cascade involving PI3K, mTOR, and the translation machinery. This mechanism of COX-2 protein induction expression in PMN is substantially different from that operative in mononuclear phagocytes, which is highly dependent on transcriptional regulation. IntroductionPMN are essential elements of the innate immune system due to their wide predominance in peripheral blood and their rapid mobilization into tissues in response to microbial infection. PMN can be activated by a variety of stimuli, which includes cytokines, IgG class antibodies, complement factors, extracellular matrix components, adhesion molecules, and microorganism constituents. This group of stimuli is of chief importance, since early protection against pathogens relies on the recognition by phagocytes of unique pattern molecules, termed pathogen-associated molecular patterns (PAMP), which are recognized through pattern-recognition receptors (PRR) by the host innate immune system. The TLR family (for review see [1, 2]), the nucleotide-binding oligomerization domain (NOD) family proteins (for review see [3][4][5]), the lectin C-type receptors such as the b-glucan receptor dectin-1 [6], and the mannose receptor (MR) family (for review see [7, 8]) include a wide array of PRR able to interact with many structural signatures expressed in microorganisms.The study of the response of PMN to PAMP has focused on the induction of cytokines, the activation of oxidant production, the release of granular components, and the modulation of apoptosis [9][10][11]. However, few data are available regarding the activation of the arachidonic acid (AA) cascade, yet this seems of interest in view of the important role of eicosanoids in connecting innate and adaptive immunity [12][13][14][15] and the attention paid to the pharmacological modulation ...

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Section: Discussionsupporting

confidence: 46%

supporting

confidence: 46%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mannan and peptidoglycan induce COX‐2 protein in human PMN via the mammalian target of rapamycin

et al. 2007

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“…Furthermore, free AA activates a variety of proteins involved in the regulation of COX-2 expression, including p38 MAP kinase (Hii et al 1998), peroxisome proliferator-activated receptor γ (Pawliczak et al 2002(Pawliczak et al , 2004 and phosphatidyl inositol-3-kinase (Monick et al 2002). Interestingly, expression of COX-2 was decreased in brains of PLA 2 -deficient mice relative to wild type mice (Bosetti and Weerasinghe, 2003).…”

Section: Discussionmentioning

confidence: 99%

2,2′,4,4′-Tetrachlorobiphenyl upregulates cyclooxygenase-2 in HL-60 cells via p38 mitogen-activated protein kinase and NF-κB

Bezdecny

Karmaus

Roth

et al. 2007

Toxicology and Applied Pharmacology

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Polychlorinated biphenyls (PCBs) are ubiquitous, persistent environmental contaminants that affect a number of cellular systems, including neutrophils. Among the effects caused by the noncoplanar PCB 2,2′,4,4′,-tetrachlorobiphenyl (2244-TCB) in granulocytic HL-60 cells are increases in superoxide anion production, activation of phospholipase A 2 with subsequent release of arachidonic acid (AA), and upregulation of the inflammatory gene cyclooxygenase-2 (COX-2). The objective of this study was to determine the signal transduction pathways involved in the upregulation of COX-2 by 2244-TCB. Treatment of HL-60 cells with 2244-TCB led to increased expression of COX-2 mRNA. This increase was prevented by the transcriptional inhibitor actinomycin D in cells pretreated with 2244-TCB for 10 minutes. The increase in COX-2 mRNA was associated with release of 3 H-AA, phosphorylation of p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinases, increased levels of nuclear NF-κB and increased superoxide anion production. Bromoenol lactone, an inhibitor of the calcium-independent phospholipase A 2 , reduced 3 H-AA release but had no effect on COX-2 mRNA, protein or activity. Pretreatment with SB-202190 or SB-203580, inhibitors of the p38 MAP kinase pathway, prevented the 2244-TCBmediated induction of COX-2 and phosphorylation of p38 and ERK MAP kinases. These inhibitors did not alter 3 H-AA release. Treatment with PD 98059 or U 0126, inhibitors of the MAP/ERK (MEK) pathway, prevented the 2244-TCB-mediated activation of ERK but had no effect on COX-2 induction or p38 phosphorylation. 2244-TCB treatment did not affect c-Jun N-terminal kinase (JNK) phosphorylation. 2244-TCB exposure increased the amount of nuclear NF-κB. This increase was prevented by pretreatment with p38 MAP kinase inhibitors, but not by pretreatment with MEK inhibitors. Pretreatment with inhibitors of NF-κB prevented the 2244-TCB-mediated induction of COX-2 mRNA. 2244-TCB-mediated increases in superoxide anion were prevented by the NADPH oxidase inhibitor apocynin or the free radical scavenger 4-hydroxy TEMPO, but neither of these inhibitors affected the 2244-TCB-induced changes in COX-2 mRNA levels or 3 H-AA release. Taken together these data suggest that p38 MAP kinase-dependent activation of NF-κB is critical for the 2244-TCB-mediated upregulation of COX-2 mRNA.

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Phosphodiesterase 4 Inhibitors in the Treatment of COPD

Tenor¹,

Bundschuh²,

Schudt³

et al. 2007

Chronic Obstructive Pulmonary Disease

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Phosphatidylinositol 3-Kinase Activity Negatively Regulates Stability of Cyclooxygenase 2 mRNA

Cited by 86 publications

References 60 publications

Mannan and peptidoglycan induce COX‐2 protein in human PMN via the mammalian target of rapamycin

Mannan and peptidoglycan induce COX‐2 protein in human PMN via the mammalian target of rapamycin

2,2′,4,4′-Tetrachlorobiphenyl upregulates cyclooxygenase-2 in HL-60 cells via p38 mitogen-activated protein kinase and NF-κB

Phosphodiesterase 4 Inhibitors in the Treatment of COPD

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