TL1A is a novel TNF-like factor that acts as a costimulator of IFN-γ secretion through binding to the death domain-containing receptor, DR3. The aim of this study was to test the hypothesis that TL1A may play an important role in inflammatory bowel disease (IBD) by functioning as a Th1-polarizing cytokine. The expression, cellular localization, and functional activity of TL1A and DR3 were studied in intestinal tissue specimens as well as isolated lamina propria mononuclear cells from IBD patients and controls. TL1A mRNA and protein expression was up-regulated in IBD, particularly in involved areas of Crohn’s disease (CD; p < 0.03 vs control). TL1A production was localized to the intestinal lamina propria in macrophages and CD4+ and CD8+ lymphocytes from CD patients as well as in plasma cells from ulcerative colitis patients. The amount of TL1A protein and the number of TL1A-positive cells correlated with the severity of inflammation, most significantly in CD. Increased numbers of immunoreactive DR3-positive T lymphocytes were detected in the intestinal lamina propria from IBD patients. Addition of recombinant human TL1A to cultures of PHA-stimulated lamina propria mononuclear from CD patients significantly augmented IFN-γ production by 4-fold, whereas a minimal effect was observed in control patients. Our study provides evidence for the first time that the novel cytokine TL1A may play an important role in a Th1-mediated disease such as CD.

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Tumor necrosis factor ␣ (TNF-␣) is an important mediator of programmed cell death, and TNF-␣ blockade significantly improves disease severity in several inflammatory conditions, including Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases. However, the precise mechanism(s) of action of anti-TNF-␣ therapy in CD remains poorly understood. SAMP1͞YitFc mice develop a spontaneous ileitis with similarities to human CD in regard to histological features as well as response to conventional treatments. In this report, we tested the novel hypothesis that the beneficial effects of anti-TNF-␣ therapy in CD are mediated by a mechanism that involves down-regulation of intestinal epithelial cell (IEC) apoptosis. Similar to the efficacy of monoclonal anti-TNF-␣ antibodies in human CD, a single injection of a chimeric anti-murine TNF-␣ antibody into SAMP1͞YitFc mice resulted in a marked suppression of intestinal inflammation and epithelial cell damage compared with mice injected with an isotype control antibody. These effects were associated with a significant reduction in apoptosis of freshly isolated IEC as assessed by propidium iodide staining and DNA laddering. In contrast, an increase in lamina propria mononuclear cell apoptosis was observed in anti-TNF-␣-treated mice compared with control. These results were confirmed in vivo by using the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-assay. In addition, neutralization of TNF-␣ reduced membrane bound FAS͞CD95 expression in IEC from SAMP1͞YitFc mice compared with control antibody. These data demonstrate a novel mechanism of action of anti-TNF-␣ therapy that involves homeostatic regulation of mucosal cell apoptosis, which results in the net decrease of chronic inflammation typically found in CD.