Clostridium difficile Toxin A Regulates Inducible Cyclooxygenase-2 and Prostaglandin E2 Synthesis in Colonocytes via Reactive Oxygen Species and Activation of p38 MAPK

Kim, Ho; Rhee, Sang Hoon; Kokkotou, Efi; Xi, Ning; Savidge, Tor; Moyer, Mary Pat; Pothoulakis, Charalabos; LaMont, J. Thomas

doi:10.1074/jbc.m413842200

Cited by 80 publications

(128 citation statements)

References 49 publications

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“…In human mesangial cells exposed to high glucose, in human monocytes undergoing differentiation, and in human fibroblasts subjected to cyclic stretch stimuli, increased COX-2 expression was dependent on generation of ROS (Amma et al 2005;Barbieri et al 2003;Kiritoshi et al 2003). These changes occurred through activation of p38 MAP kinase and a variety of transcription factors including NF-κB (Amma et al 2005;Kim et al 2005;Singer et al 2003). In the present study, 2244-TCB caused an increase in superoxide anion production, similar to results reported previously for rat neutrophils (Ganey et al 1993).…”

Section: Discussionsupporting

confidence: 89%

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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Section: Discussionsupporting

confidence: 89%

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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“…In this study, we also demonstrated that cell-densitydependent hypoxia enhances the DNA-binding activity of AP-1 in nuclear extracts from the hypoxic NIH3T3 fibroblasts, whereas the binding activities of NF-kB, SP-1 and CREB were not influenced by the hypoxic stimulation, although all of these transcriptional factors are reported to be required for COX-2 expression (Xie and Herschman, 1996;Schmedtje et al, 1997;Smith et al, 2000;Xu et al, 2000;Liu et al, 2003;Kim et al, 2005). Furthermore, the hypoxia-mediated DNA-binding activity of AP-1 was diminished by the treatment with AP-1 inhibitor, curcumin (Huang et al, 1991;Lu et al, 1994;Tanaka et al, 2004;Park et al, 2005), followed by the reduction of COX-2 expression in NIH3T3 cells.…”

Section: Hypoxia Induces Stromal Cyclooxygenase-2mentioning

confidence: 75%

Hypoxia induced by benign intestinal epithelial cells is associated with cyclooxygenase-2 expression in stromal cells through AP-1-dependent pathway

et al. 2006

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Cyclooxygenase-2 (COX-2) plays important roles in tumor development. Especially in the early-stage colorectal tumors, COX-2 expression is often observed in the tumor stroma. However, the mechanism regulating such stromal expression of COX-2 remains unknown. In the present study, we simulated the indirect interaction between epithelial cells and stromal cells in the process of colorectal tumor development using an in vitro co-culture model in which NIH3T3 fibroblasts were co-cultured with 'sparsely' or 'densely' populated intestinal epithelial cells, Intestine-407 as a model of premalignant or benign intestinal epithelial cells, and DLD-1 and Caco-2 as models of malignant epithelial cells. COX-2 expression in NIH3T3 fibroblasts was upregulated when co-cultured with the 'dense' epithelial cells regardless of their character. Interestingly, there was pericellular hypoxia in the vicinity of NIH3T3 fibroblasts when cocultured with 'dense' epithelial cells, and the recovery of the partial pressure of oxygen level resulted in the reduction of enhanced COX-2 expression only in NIH3T3 fibroblasts co-cultured with 'dense' Intestine-407 cells. Furthermore, COX-2 expression was also reduced by the inhibition of transcription factor AP-1. Thus, pericellular hypoxia of the stromal cells caused by densely populated epithelial cells may be one of the potent COX-2 enhancers before completion of malignant transformation during intestinal tumor development.

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“…We also present evidence that Jak2 upstream of Akt is involved in this SP response. Interestingly, Jak2 was recently shown to also mediate cyclooxygenase 2 (COX-2) gene up-regulation and prostaglandin E 2 release in human colonocytes exposed to SP (27) and evidence was presented indicating that COX-2 promotes intestinal inflammatory responses (39). Thus, SP-induced Jak2 phosphorylation may mediate both proinflammatory and antiapoptotic signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

Koon

Zhao

Zhan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

100

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We examined the hypothesis that substance P (SP) and the neurokinin-1 receptor (NK-1R), both in vitro and in vivo, promote mucosal healing during recovery from colitis by stimulating antiapoptotic pathways in human colonic epithelial cells. For the in vitro experiments, human nontransformed NCM460 colonocytes stably transfected with NK-1R (NCM460-NK-1R cells) were exposed to SP, and cell viability assays, TUNEL assays, and Western blot analyses were used to detect apoptotic and antiapoptotic pathways. SP exposure of NCM460-NK-1R colonocytes stimulated phosphorylation of the antiapoptotic molecule Akt and inhibited tamoxifeninduced cell death and apoptosis evaluated by the cell viability assay and poly(ADP-ribose) polymerase cleavage, respectively. SP-induced phosphorylation of Akt and cleavage of poly(ADPribose) polymerase were inhibited by blockade of integrin ␣V␤3, Jak2, and activation of phosphatidylinositol 3-kinase. For the in vivo experiments, C57BL/6 mice, administered 5% dextran sulfate (DSS) dissolved in tap water for 5 days followed by a 5-day recovery period, were treated with the NK-1R antagonist CJ-12,255 or vehicle. Vehicle-treated mice showed increased colonic Akt phosphorylation and apoptosis compared with mice that received no DSS. In contrast, daily i.p. administration of CJ-12,255 for 5 days post-DSS suppressed Akt activation, exacerbated colitis, and enhanced apoptosis, and pharmacologic inhibition of Akt, either alone or together with CJ-12,255, produced a similar effect. Thus, SP, through NK-1R, possesses antiapoptotic effects in the colonic mucosa by activating Akt, which prevents apoptosis and mediates tissue recovery during colitis.apoptosis ͉ colitis

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Clostridium difficile Toxin A Regulates Inducible Cyclooxygenase-2 and Prostaglandin E2 Synthesis in Colonocytes via Reactive Oxygen Species and Activation of p38 MAPK

Cited by 80 publications

References 49 publications

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

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

Hypoxia induced by benign intestinal epithelial cells is associated with cyclooxygenase-2 expression in stromal cells through AP-1-dependent pathway

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

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