Rapid development of colitis in NSAID-treated IL-10–deficient mice

Berg, Daniel J.; Zhang, Juan; Weinstock, Joel V.; Ismail, Hanan F.; Earle, Keith A.; Alila, Hector W.; Pamukcu, Rifat; Moore, Steven A.; Lynch, Richard G.

doi:10.1053/gast.2002.1231527

Cited by 248 publications

(250 citation statements)

References 60 publications

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“…Hence, it is apparent that COX-2 is at least one of the cell survival effectors downstream of EGFR transactivation by TNF; however, further experiments are needed to confirm such a role for COX-2 in vivo. The survival role of COX-2 in an environment of high TNF concentration may explain why nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors, can exacerbate IBD (7,18,31,42,51). For instance, administration of selective COX-2 inhibitors to IL-10 Ϫ/Ϫ mice that develop spontaneous colitis, in which TNF levels are elevated (6) and demonstrably critical to the progression of the colitis (56), augmented the severity of colitis (25).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The model chosen was piroxicam-induced, IL-10 Ϫ/Ϫ colitis (14). IL-10 Ϫ/Ϫ mice develop chronic colitis that gradually worsens as the animals age.…”

Section: Discussionmentioning

confidence: 99%

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

Weinstock

Blum

Metwali

et al. 2003

The Journal of Immunology

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Substance P (SP) is a proinflammatory molecule that interacts with a neurokinin 1 receptor (NK-1R), which is on T cells and helps control IFN-γ production. IL-10−/− mice given a nonsteroidal anti-inflammatory drug (NSAID) develop Th1 colitis. We studied the importance of SP and NK-1R in this colitis model. LP T cells were isolated to study their NK-1R expression. LP T cells from IL-10−/− mice expressed NK-1R and produced IFN-γ only after NSAID treatment and induction of colitis. LP T cells from NSAID-treated wild-type controls or from age-matched untreated IL-10−/− animals did not express NK-1R or produce IFN-γ. Experiments showed that IL-12 induced NK-1R transcription in CD4+ T cells cultured in vitro. However, T cells cultured with IL-12 and IL-10 did not express NK-1R. IL-10 also down-modulated ongoing NK-1R expression. Mice given NK-1R antagonist after NSAID induction of severe colitis showed nearly complete reversal of inflammation, and LP T cells ceased IFN-γ secretion. Thus, intestinal inflammation in IL-10−/− mice is associated with the appearance of NK-1R in mucosal T cells, and an interplay between IL-12 and IL-10 regulates T cell NK-1R transcription. NK-1R antagonist reverses ongoing intestinal inflammation attesting to the importance of SP and its receptor in mucosal inflammation.

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“…To explore the effect of an acute gut inflammation on IEL snatching of TL, we used a model system in which B6 mice with a targeted disruption of the IL-10 gene (IL-10 Ϫ/Ϫ ) develop spontaneous chronic inflammatory bowel disease characterized by increased inflammatory cytokine production as well as IFN-␥ from Th1 CD4 ϩ T cells (15,16). This process is hastened by treating mice with piroxicam, a nonsteroidal anti-inflammatory drug (17).…”

Section: Gut Inflammation Induces Tl Snatching In Vivomentioning

confidence: 99%

CD8αα-Mediated Intraepithelial Lymphocyte Snatching of Thymic Leukemia MHC Class Ib Molecules In Vitro and In Vivo

Pardigon

Takeda

Saunier

et al. 2006

The Journal of Immunology

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Thymic leukemia (TL) is a MHC class Ib molecule that interacts with CD8αα homodimers. CD8αα is abundantly expressed by intraepithelial T lymphocytes (IELs) located in close proximity to TL-expressing intestinal epithelial cells. In this study, we show that CD8αα+ IELs “snatch” TL from the plasma membrane of TL-expressing cells and express TL in its proper orientation on their own cell surface. TL snatching is enhanced by cross-linking of IEL TCRs in a phosphatidylinositol kinase-dependent manner, and results in overall alterations to the IEL cell surface detected by enhanced binding of peanut agglutinin lectin. Induction of bowel inflammation results in the presence of TL on IELs, probably via in vivo snatching, providing the initial evidence for the interaction of CD8αα IELs with intestinal cells.

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Rapid development of colitis in NSAID-treated IL-10–deficient mice

Cited by 248 publications

References 60 publications

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

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

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

CD8αα-Mediated Intraepithelial Lymphocyte Snatching of Thymic Leukemia MHC Class Ib Molecules In Vitro and In Vivo

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