Regulation of COX-2 expression in human intestinal  myofibroblasts: mechanisms of IL-1-mediated induction

Mifflin, Randy C.; Saada, Jamal I.; Mari, John F. Di; Adegboyega, Patrick A.; Valentich, J. D.; Powell, Don W.

doi:10.1152/ajpcell.00388.2001

Cited by 130 publications

(96 citation statements)

References 61 publications

(74 reference statements)

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“…Furthermore, IL-1␣ enhanced TGF-␣-stimulated cell migration in a synergistic manner, mimicking the effect of PGE 2 (34). COX-2/PGE 2 signaling plays critical roles in neoangiogenesis; homozygous deletion of EP 2 R significantly reduces the number and size of intestinal polyps in APC ⌬716 mice that is associated with a reduction of VEGF expression, suggesting that PGE 2 /EP 2 signaling is critical for increased levels of VEGF in intestinal neoplasm (19 4 receptors are coupled to stimulatory G (G s ) proteins and signal through increased cAMP, whereas the EP 3 R is coupled to inhibitory G (G i ) proteins which inhibit the generation of cAMP. PGE 2 stimulates the transcription of a number of genes through the cAMP/PKA pathway where the cAMP responsive element (CRE) within the promoter plays critical roles (13,41).…”

Section: Discussionmentioning

confidence: 98%

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Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

Shao

Sheng

2007

The Journal of Immunology

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PGE2 has been shown to exert pro-oncogenic effects in colorectal neoplasia through producing autocrine or paracrine growth factors. In the present study, we demonstrate that PGE2 induced the expression of IL-1α in colon cancer cells, which plays critical roles in tumor metastasis and neoangiogenesis in a variety of cancers. PGE2 increased the levels of both IL-1α mRNA and protein, suggesting a positive feedback loop between the IL-1 pathway and PGE2 signaling. Mechanistically, PGE2 induced the expression of IL-1α at both transcriptional and posttranscriptional levels. PGE2 stimulated the transcriptional activity of the IL-1α promoter and significantly stabilized IL-1α mRNA. Moreover, we show that IL-1α enhanced colorectal neoplasia, stimulating cell migration and neoangiogenesis. Knockdown of the expression of IL-1α by small-interfering RNA resulted in a reduction of vascular endothelial growth factor secretion in colon cancer cells and an inhibition of tube formation by HUVECs. Thus, our results suggest that PGE2 induces the expression of proinflammatory cytokine IL-1α, which may potentially enhance the proneoplastic actions of the cyclooxygenase-2/PGE2 signaling pathway.

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Section: Discussionmentioning

confidence: 98%

“…The proinflammatory activities of IL-1 result largely from stimulating the expression of genes encoding inflammatory mediators. It is well-documented that IL-1 increases the expression of cyclooxygenase-2 (COX-2) 3 and the production of PGE 2 (3,4). Many biological activities of IL-1 are actually due to increased PGE 2 production (5).…”

mentioning

confidence: 99%

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

Shao

Sheng

2007

The Journal of Immunology

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“…has been previously demonstrated to stabilize multiple mRNA species, such as COX-2 [42,43,[62][63][64], IL-8 [56] and NGF [65,66]. Importantly, it has already been reported that IL-1β stabilizes IL-6 mRNA in osteoblasts [16,35], fibroblasts [9], myofibroblasts [14], astrocytes [36] and fibroblast-like synoviocytes [12], although relatively little was known about the molecular mechanisms underlying this stabilization.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, both can be activated by IL-1β and have been convincingly implicated in COX-2 mRNA stabilization [21,31,[41][42][43][44][45][46]. Moreover, in multiple studies, IL-1β-induced mRNA stabilization of IL-6 was shown to be crucially dependent on p38 [12,16], whereas dependence on PKC has not yet been described.…”

Section: Page 14 Of 48mentioning

confidence: 99%

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined β-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a β-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-α and IL-1β. We found that IL-1β treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNAstabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL-6 mRNA, the mRNA-stabilizing effect of IL-1β is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications.

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“…Western blot analysis was performed as previously described (40). Briefly, cells were washed with ice-cold PBS and lysed in Laemmli sample buffer (10% glycerol, 5% 2-ME, 2% SDS, 0.002% bromphenol blue, and 62.5 mM Tris-HCl (pH 6.8)).…”

Section: Western Blot Analysismentioning

confidence: 99%

Subepithelial Myofibroblasts are Novel Nonprofessional APCs in the Human Colonic Mucosa

Saada¹,

Pinchuk²,

Barrera³

et al. 2006

The Journal of Immunology

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109

139

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The human gastrointestinal mucosa is exposed to a diverse normal microflora and dietary Ags and is a common site of entry for pathogens. The mucosal immune system must respond to these diverse signals with either the initiation of immunity or tolerance. APCs are important accessory cells that modulate T cell responses which initiate and maintain adaptive immunity. The ability of APCs to communicate with CD4+ T cells is largely dependent on the expression of class II MHC molecules by the APCs. Using immunohistochemistry, confocal microscopy, and flow cytometry, we demonstrate that α-smooth muscle actin+, CD90+ subepithelial myofibroblasts (stromal cells) constitutively express class II MHC molecules in normal colonic mucosa and that they are distinct from professional APCs such as macrophages and dendritic cells. Primary isolates of human colonic myofibroblasts (CMFs) cultured in vitro were able to stimulate allogeneic CD4+ T cell proliferation. This process was dependent on class II MHC and CD80/86 costimulatory molecule expression by the myofibroblasts. We also demonstrate that CMFs, engineered to express a specific DR4 allele, can process and present human serum albumin to a human serum albumin-specific and DR4 allele-restricted T cell hybridoma. These studies characterize a novel cell phenotype which, due to its strategic location and class II MHC expression, may be involved in capture of Ags that cross the epithelial barrier and present them to lamina propria CD4+ T cells. Thus, human CMFs may be important in regulating local immunity in the colon.

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Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction

Cited by 130 publications

References 61 publications

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Subepithelial Myofibroblasts are Novel Nonprofessional APCs in the Human Colonic Mucosa

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