benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone has been researched along with Colitis* in 2 studies
2 other study(ies) available for benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Colitis
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Non-apoptotic function of caspases in a cellular model of hydrogen peroxide-associated colitis.
Oxidative stress, caused by reactive oxygen species (ROS), is a major contributor to inflammatory bowel disease (IBD)-associated neoplasia. We mimicked ROS exposure of the epithelium in IBD using non-tumour human colonic epithelial cells (HCEC) and hydrogen peroxide (H2 O2 ). A population of HCEC survived H2 O2 -induced oxidative stress via JNK-dependent cell cycle arrests. Caspases, p21(WAF1) and γ-H2AX were identified as JNK-regulated proteins. Up-regulation of caspases was linked to cell survival and not, as expected, to apoptosis. Inhibition using the pan-caspase inhibitor Z-VAD-FMK caused up-regulation of γ-H2AX, a DNA-damage sensor, indicating its negative regulation via caspases. Cell cycle analysis revealed an accumulation of HCEC in the G1 -phase as first response to oxidative stress and increased S-phase population and then apoptosis as second response following caspase inhibition. Thus, caspases execute a non-apoptotic function by promoting cells through G1 - and S-phase by overriding the G1 /S- and intra-S checkpoints despite DNA-damage. This led to the accumulation of cells in the G2 /M-phase and decreased apoptosis. Caspases mediate survival of oxidatively damaged HCEC via γ-H2AX suppression, although its direct proteolytic inactivation was excluded. Conversely, we found that oxidative stress led to caspase-dependent proteolytic degradation of the DNA-damage checkpoint protein ATM that is upstream of γ-H2AX. As a consequence, undetected DNA-damage and increased proliferation were found in repeatedly H2 O2 -exposed HCEC. Such features have been associated with neoplastic transformation and appear here to be mediated by a non-apoptotic function of caspases. Overexpression of upstream p-JNK in active ulcerative colitis also suggests a potential importance of this pathway in vivo. Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Caspases; Cell Cycle; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Colitis; Colon; Comet Assay; DNA Damage; Epithelial Cells; Histones; Humans; Hydrogen Peroxide; Immunohistochemistry; Inflammation; Inflammatory Bowel Diseases; MAP Kinase Kinase 4; Oxidative Stress; Reactive Oxygen Species; Subcellular Fractions | 2013 |
Remission-inducing effect of anti-TNF monoclonal antibody in TNBS colitis: mechanisms beyond neutralization?
Tumor necrosis factor (TNF) plays an important role in the pathogenesis of several inflammatory diseases. Its expression is increased in inflamed mucosa of Crohn's disease patients and anti-TNF treatment improves mucosal inflammation. Besides neutralization, induction of apoptosis of monocytes/macrophages and T cells is thought to be an important mechanism of action of the anti-TNF monoclonal antibody therapy. The aim was to investigate the pathogenic role of TNF in hapten-induced colitis models and to study the relationship between apoptosis induction and disease remission.. In 2 murine colitis models (trinitrobenzene sulphonic acid, TNBS, and oxazolone colitis), mice were injected daily with anti-TNF monoclonal antibody (mAb). Macrophages were collected from lamina propria of TNBS colitis mice. 7AAD and anti-active-caspase-3 staining were used to study DNA degradation and intracellular caspase activation. A pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), was given to a subgroup of the colitis mice.. Treatment with anti-TNF effectively reduced intestinal mucosal inflammation in TNBS colitis but not in oxazolone colitis. Effectiveness was evidenced by a more rapid recovery of body weight and reduced cell infiltration, and downregulation of proinflammatory cytokines interferon-gamma (IFN-gamma), TNF, and IL-18 at the mRNA level. Apoptosis was induced in lamina propria macrophages after treatment with anti-TNF, and it was abrogated through short-term pretreatment with Z-VAD-FMK.. Anti-TNF downregulates proinflammatory cytokines and decreases cell infiltration in the bowel after TNBS application. The remission-inducing effect of anti-TNF may partly rely on apoptosis induction. Topics: Amino Acid Chloromethyl Ketones; Animals; Antibodies, Monoclonal; Apoptosis; Caspase Inhibitors; Colitis; Down-Regulation; Inflammatory Bowel Diseases; Infliximab; Interferon-gamma; Interleukin-18; Male; Mice; Mice, Inbred C57BL; Oxazolone; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha | 2007 |