Sustained Polymorphonuclear Leukocyte Transmigration Induces Apoptosis in T84 Intestinal Epithelial Cells (original) (raw)
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Inflammatory Bowel Diseases, 2013
The inflammatory bowel diseases (IBD; Crohn's disease and ulcerative colitis) are chronically relapsing, inflammatory disorders of the intestine and/or colon. The precise etiology of IBD remains unclear, but it is thought that a complex interplay between various factors including genetic predisposition, the host immune system, and the host response to luminal microbes play a role in disease pathogenesis. Further, numerous lines of evidence have implicated the accumulation of large numbers of PMN in the mucosa and epithelial crypts of the intestine as a hallmark of the active disease phase of IBD. Massive infiltration of PMNs is thought to be instrumental in the pathophysiology of IBD with the degree of PMN migration into intestinal crypts correlating with patient symptoms and mucosal injury. Specifically, migrated PMN have been implicated in the impairment of epithelial barrier function, tissue destruction via oxidative and proteolytic damage, and the perpetuation of inflammation through the release of inflammatory mediators. This review highlights the multifactorial role of PMN egress into the intestinal mucosa in the pathogenesis of IBD, as it represents an important area of research with therapeutic implications for the amelioration of the symptoms associated with IBD.
American journal of physiology. Gastrointestinal and liver physiology, 2002
The regulatory mechanisms of nontransformed intestinal epithelial cell apoptosis have not been thoroughly investigated. We determined the susceptibility and mechanism of Fas-mediated apoptosis in nontransformed human intestinal epithelial cells (HIPEC) in the presence and absence of inflammatory cytokines. Despite ample expression of Fas, HIPEC were relatively insensitive to Fas-mediated apoptosis in that agonist anti-Fas antibody (CH11) induced a <25% increase in HIPEC apoptosis. Pretreatment of HIPEC with interferon (IFN)-gamma, but not tumor necrosis factor-alpha or granulocyte-macrophage colony-stimulating factor, significantly increased CH11-induced apoptosis of these cells without increasing Fas expression. Increased apoptosis correlated with increased caspase 3 activation but not expression of procaspase 3. Also, there was a significant delay in the onset of Fas-mediated apoptosis in HIPEC, which correlated with the generation of an activated caspase 3 p22/20 subunit. HIPE...
Leukocyte migration in experimental inflammatory bowel disease
Mediators of Inflammation, 1997
EMIGRATION of leukocytes from the circulation into tissue by transendothelial migration, is mediated subsequently by adhesion molecules such as selectins, chemokines and integrins. This multistep paradigm, with multiple molecular choices at each step, provides a diversity in signals. The in ux of neutrophils, monocytes and lymphocytes into in amed tissue is important in the pathogenesis of chronic in ammatory bowel disease. The importance of each of these groups of adhesion molecules in chronic in ammatory bowel disease, either in human disease or in animal models, will be discussed below. Furthermore, the possibilities of blocking these different steps in the process of leukocyte ex travasation in an attempt to prevent further tissue damage, will be taken into account.
International Journal of Colorectal Disease, 2005
Abnormal apoptosis may result in the persistence of activated intestinal T-cells in inflammatory bowel disease (IBD). We investigated apoptosis in distinct mucosal compartments, and the expression of Fas/Fas ligand and perforin in the inflamed and noninflamed intestinal mucosa of patients with IBD. Methods: Colon specimens from 15 patients with ulcerative colitis (UC) and inflamed and non-inflamed mucosa from 15 patients with Crohn's disease (CD) were analysed for densities and distribution of apoptotic cells determined by the terminal deoxynucleotidyltransferase-mediated dUDPbiotin nick-end labelling (TUNEL) method. Fas, FasL, and perforin-expressing cells were assessed by immunoperoxidase, and with anti-CD3, anti-CD20 and anti-CD68, by double immunofluorescence with confocal microscopy. Quantitative analysis was performed using a computer-assisted image analyser. Results: Colonic lamina propria (LP) and epithelium from patients with UC showed higher rates of apoptosis than controls, but no difference was shown regarding patients with CD. In LP, co-expression of Fas was reduced with T-cells in inflamed CD mucosa, and with macrophages in all patients with IBD. No difference was found in the expression of Fas on B-cells. Rates of FasL-expressing cells in LP were higher in IBD than in controls, with no correlation with the rates of apoptosis. Rates of perforin-expressing cells in LP were greater in UC than in controls, and correlated to the rates of apoptosis. No difference was shown regarding the inflamed and non-inflamed CD mucosa. Rates of FasL and perforinexpressing intra-epithelial lymphocytes showed no difference among groups. Conclusions: Increased expression of FasL in IBD colonic LP not parallelled by Fas on T-cells and macrophages may indicate a reduced susceptibility to the Fas/FasL-mediated apoptosis of lymphoid cells. Expression of perforin is correlated to the tissue damage, and may represent the enhancement of a distinct cytotoxic pathway in UC.
Immunology, 2004
Poly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA injury in the nucleus of eukaryotic cells and has been implicated in intestinal barrier dysfunction during inflammatory bowel diseases. In this study we investigated whether PARP-1 may regulate the inflammatory response of experimental colitis at the level of signal transduction mechanisms. Mice genetically deficient of PARP-1 (PARP-1 -/-) and wild-type littermates were subjected to rectal instillation of trinitrobenzene sulphonic acid (TNBS). Signs of inflammation were monitored for 14 days. In wild-type mice, TNBS treatment resulted in colonic ulceration and marked apoptosis, which was associated with decreased colon content of the antiapoptotic protein Bcl-2, whereas the proapoptotic Bax was unchanged. Elevated levels of plasma nitrate/nitrite, metabolites of nitric oxide (NO), were also found. These inflammatory events were associated with activation of c-Jun-NH 2 terminal kinase (JNK), phosphorylation of c-Jun and activation of the nuclear transcription factor activator protein-1 (AP-1) in the colon. In contrast, PARP-1 -/mice exhibited a significant reduction of colon damage and apoptosis, which was associated with increased colonic expression of Bcl-2 and lower levels of plasma nitrate/nitrite when compared to wild-type mice. Amelioration of colon damage was associated with a significant reduction of the activation of JNK and reduction of the DNA binding of AP-1. The data indicate that PARP-1 exerts a pathological role in colitis possibly by regulating the early stress-related transcriptional response through a positive modulation of the AP-1 and JNK pathways.
Clinical and Experimental Immunology, 2005
Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharides, plays an important role in the innate immune response. In this study, we investigated the role of TLR4 in the development of experimental colitis with regard to the biological actions of macrophage migration inhibitory factor (MIF) using TLR4 null ( -/-) mice. TLR4 -/mice were given 2% dextran sulphate sodium (DSS) in drinking water to induce colitis, which was clinically and histologically as severe as that seen in wild-type (WT) mice. The level of tumour necrosis factor (TNF)-a a a a in colon tissues was increased in WT mice but unchanged in TLR4 -/mice. The level of myeloperoxidase (MPO) activity in colon tissues was increased by DSS administration in both TLR4 -/and WT mice. The expression of MIF was up-regulated in the colons of TLR4 -/mice with acute DSS-induced colitis. An anti-MIF antibody significantly suppressed colitis and elevation of matrix metalloproteinase-13 in TLR4 -/mice. The current results obtained from TLR4 -/mice provide evidence that MIF plays a critical role in the development of acute DSS-induced colitis.
Leukotrienes induce cell-survival signaling in intestinal epithelial cells
Gastroenterology, 2000
Background&Aims: Inflammatory bowel conditions, particularly ulcerative colitis, are associated with an increased incidence of neoplastic transformation. High levels of proinflammatory leukotrienes (LTs) and upregulated expression of cyclooxygenase (COX)-2 are characteristic of inflammation. Moreover, COX-2 has been implicated in cell survival and early colon carcinogenesis. Other aspects of interest for intestinal cell viability are the levels of I~-catenin and the antiapoptotic protein Bcl-2. We investigated the possibility that LTs participate in the regulation of these survival factors. Methods: We used the human intestinal epithelial cell line Int 407 and the rat intestinal epithelial cell line IEC-6. Immunoblotting was applied to ascertain protein expression and distribution, and enzyme immunoassay methodology was used to measure prostaglandin E2 (PGE2) production. Apoptotic ability was assessed by trypan blue exclusion, Hoechst staining, DNA fragmentation, and a caspase-3 activity assay. Results: LTD4 and LTB4, but not LTC4, caused a time-and dose-dependent increase in expression and/or membrane accumulation of COX-2, 13-catenin, and Bcl-2, as well as PGE2 production. Apoptosis assays showed that the effects of LTs on these transformation-associated proteins correlated well with the ability of these LTs to reduce programmed cell death. Conclusions: The results suggest that inflammatory conditions are associated with the expression and distribution of proteins that are characteristic of transformed cells; such conditions may involve a signaling mechanism comprising an altered rate of apoptosis. Recently, Sheng et al. ~5 observed that COX-2 and Bcl-2 are up-regulated simultaneously in human colon
Digestive diseases and …, 2005
It is known that bacterial chemotactic peptides such as formyl-methionyl-leucyl-phenylalanine (fMLP) exacerbate colitis during the acute phase, but the precise role of fMLP during chronic "relapse" is unknown. In this study we examined the effect of bacterial peptides in animal models of acute and chronic "relapsed" colitis. Different parameters were evaluated, such as tissue damage, myeloperoxidase activity, and mucosal function. In acute trinitrobenezene sulfonic acid colitis, fMLP had significant adverse effects on mucosal function and worsened several parameters. In contrast, in chronic "relapsed" colitis the ability of fMLP to exacerbate the inflammation was dependent on whether it was confined to the lumen of the colon. Bacterial peptides such as fMLP appear to play a different role in the acute phase of inflammation compared with the chronic phase, depending on the integrity of the mucosal barrier.