Prostaglandins and activation of AC/cAMP prevents anoikis in IEC-18

Joseph, Robbie R.; Yazer, E.; Hanakawa, Yasushi; Stadnyk, Andrew W.

doi:10.1007/s10495-005-2049-y

Cited by 27 publications

(17 citation statements)

References 44 publications

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“…We have isolated colonocytes from the normal-appearing margins of human cancer resections and observed these cells rapidly succumb to apoptosis when prepared in single cell suspension. None of the strategies in which we are aware will delay apoptosis of detached IEC-18 in culture (42) work to keep human colonocytes viable, and indeed these cells are refractory to IL-1 and TNF-␣.…”

Section: Discussionmentioning

confidence: 99%

Differential Pattern of Inflammatory Molecule Regulation in Intestinal Epithelial Cells Stimulated with IL-1

Yan

Joseph

Wang

et al. 2006

The Journal of Immunology

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To better predict the consequences of blocking signal transduction pathways as a means of controlling intestinal inflammation, we are characterizing the pathways up-regulated by IL-1 in intestinal epithelial cells (IEC). IL-1β induced increased mRNA levels of MIP-2, MCP-1, RANTES, inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) in the IEC-18 cell line. IL-1β activated NF-κB but not ERK or p38. Infecting cells with adenovirus expressing a mutated gene for IκBα (IκBAA) blocked IL-1-induced mRNA increases in MIP-2, MCP-1, and iNOS but not COX-2 or RANTES. Expression of IκBAA attenuated the IL-1-induced increase in COX-2 protein. Unexpectedly, RANTES mRNA increased, and protein was secreted by cells expressing IκBAA in the absence of IL-1. Adenovirus-expressing IκBAA, blocking protein synthesis, and IL-1β all resulted in activation of JNK. The JNK inhibitor SP600125 prevented the RANTES increases by all three stimuli. A human enterocyte line was similarly examined, and both NF-κB and JNK regulate IL-1-induced RANTES secretion. We conclude that in IEC-18, IL-1β-induced increases in mRNA for MIP-2, MCP-1, and iNOS are NF-κB-dependent, whereas regulation of RANTES mRNA is independent of NF-κB but is positively regulated by JNK. IL-1β-induced mRNA increases in COX-2 mRNA are both NF-κB- and MAPK-independent but the translation of COX-2 protein is NF-κB-dependent. This pattern of signaling due to a single stimulus exposed the complexities of regulating inflammatory genes in IEC.

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Section: Discussionmentioning

confidence: 99%

Differential Pattern of Inflammatory Molecule Regulation in Intestinal Epithelial Cells Stimulated with IL-1

Yan

Joseph

Wang

et al. 2006

The Journal of Immunology

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“…Through generation of PGs, COX-2 regulates diverse biological responses, including cell survival (28,68,71), proliferation (58), and migration (10), that promote homeostasis of the colon epithelial monolayer. COX-2 is thought to be important in IBD, because COX-2 protein expression and PG levels are elevated in the GI tract of IBD patients (32,59,62).…”

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confidence: 99%

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Hobbs¹,

Goettel

Liang³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2−/−mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1−/−cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR−/−and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFRwa2and EGFRwa5, mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.

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“…Functionally, PGE 2 interacts with the four receptor subtypes (EP1-4). EP1 and EP3 primarily contribute to inflammatory responses, whereas EP4 promotes both cell survival and growth by activating antiapoptotic and proliferative cellular signaling pathways (Fujino et al, 2003;Hase et al, 2003;Hoshino et al, 2003;Goulet et al, 2004;Joseph et al, 2005). Moreover, EP4 is constitutively expressed in the colonic epithelium and further induced during IBD, along with PGE 2 (WiercinskaDrapalo et al, 1999;Northey et al, 2000;Takafuji et al, 2000;Nitta et al, 2002).…”

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confidence: 99%

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

Jiang¹,

Nieves²,

Im³

et al. 2006

J Pharmacol Exp Ther

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Inflammatory bowel disease (IBD) is often triggered and/or exacerbated by nonsteroidal anti-inflammatory drugs (NSAIDs). Among various prostanoids affected by NSAIDs, prostaglandin E 2 (PGE 2 ), in particular, seems to play critical roles in IBD via the EP4 receptor, one of the four PGE 2 receptor subtypes (EP1-4). An EP4 agonist, [[3-[[(1R,2S,3R)(ONO-AE1-329), for example, when topically applied, has been reported to ameliorate typical colitis symptoms by suppressing the production of cytotoxic cytokines in the dextran sodium sulfate (DSS)-induced colitis model. EP4 agonists are also known, however, for their ability to protect epithelial cells from apoptosis in vitro, which may contribute to the protection of mucosal barrier functions. To investigate this potential application, we have tested another EP4-selective agonist in the DSS-indomethacin mouse colitis model. 7-[2-(3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester, C 23 H 33 NO 4 (AGN205203), an analog from the 8-azapiperidinone series of EP4 agonists, is metabolically and chemically more stable than the ONO agonist, because of its lack of oxidizable sulfur atoms in the ␣-chain and of 11-OH group, a potential source of ␤-elimination reaction. Treatment of mice subcutaneously with AGN205203 at 3 mg/kg/day minimized colitis symptoms, such as weight loss, diarrhea, and colonic bleeding. Further histological examination of colons revealed healthy surface columnar epithelial cells free of erosion and ulceration compared with those without the drug treatment. At cellular level, the drug treatment decreased colon epithelial apoptosis, prevented goblet cell depletion, and promoted epithelial regeneration. AGN205203 may be unique among known EP4 agonists for its metabolic and chemical stability, and it is amenable to systemic applications for the prevention and recovery of IBD.Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), affect approximately 1.4 million United States patients with 15,000 to 30,000 new cases annually at a mean age between 30s and early 40s. IBD patients suffer from body weight loss, diarrhea, fecal blood, and pain. Such symptoms could last for 15 to 25 years, frequently alternating between exacerbation and remission, thus severely affecting the quality of patient life and retarding the growth of young patients (Loftus, 2004;Isaacs et al., 2005). General consensus in the field is that IBD may arise from compromised colonic mucosal barrier functions that allow colonic antigens access to submucosal monocytes, which, upon activation, initiate innate immune responses and trigger cytotoxic cytokine production. Prevention and recovery of IBD thus largely depend on the integrity and maintenance of colonic mucosal barrier functions, which are compromised by inflammations along the entire bowel wall in CD and at the mucosal surface in UC.Current therapies primarily aim at the symptomatic remission by anti-inflammatory agents such as aminosalicylates and/or immunosuppres...

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Prostaglandins and activation of AC/cAMP prevents anoikis in IEC-18

Cited by 27 publications

References 44 publications

Differential Pattern of Inflammatory Molecule Regulation in Intestinal Epithelial Cells Stimulated with IL-1

Differential Pattern of Inflammatory Molecule Regulation in Intestinal Epithelial Cells Stimulated with IL-1

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration

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