Opposite Role of Tumor Necrosis Factor Receptors in Dextran Sulfate Sodium-Induced Colitis in Mice

Abstract

Tumor necrosis factor-α (TNF-α) is a key factor for the pathogenesis of inflammatory bowel diseases (IBD), whose function is known to be mediated by TNF receptor 1 (TNFR1) or 2. However, the precise role of the two receptors in IBD remains poorly understood. Herein, acute colitis was induced by dextran sulfate sodium (DSS) instillation in TNFR1 or 2−/− mice. TNFR1 ablation led to exacerbation of signs of colitis, including more weight loss, increased mortality, colon shortening and oedema, severe intestinal damage, and higher levels of myeloperoxidase compared to wild-type counterparts. While, TNFR2 deficiency had opposite effects. This discrepancy was reflected by alteration of proinflammatory cytokine and chemokine production in the colons. Importantly, TNFR1 ablation rendered enhanced apoptosis of colonic epithelial cells and TNFR2 deficiency conferred pro-apoptotic effects of lamina propria (LP)-immune cells, as shown by the decreased ratio of Bcl-2/Bax and enhanced nuclear factor (NF)-κB activity.

Protective role of tumor necrosis factor (TNF) receptors in chronic intestinal inflammation: TNFR1 ablation boosts systemic inflammatory response

“…Thus, it is plausible that TNF signaling via TNFR2 have distinct effects on the acute phase and long-term phase of intestinal inflammation, which may be attributed to the different cell types in charge of delivering TNFR2-mediated signals at different stages of inflammation. In fact, although TNFR2 is broadly expressed by colonic epithelial cells and lamina propria (LP) immune cells, TNFR2-dependent signaling in LP immune cells had dominant role during acute inflammation, 13 whereas its pro-apoptotic signaling in epithelial cells might be crucial in the progression of chronic colitis as shown in this paper. On the other hand, the role of TNFR1-mediated signaling in intestinal inflammation also remains to be confusing.…”

“…In contrast to those with acute colitis, which exhibited profound weight loss, 13 WT mice suffering from chronic colitis had no significant loss of body weight, compared with WT controls (Figure 1a). TNFR1 À / À and TNFR2 À / À mice, however, harbored 60.74±7.92% and 60.87±9.61% of the weight of WT counterparts, respectively, on day 78 after initiation of drinking DSS (Figure 1a).…”

“…TNFR1 À / À Balb/c mice displayed more severe mucosal damage, whereas TNFR2 knockout led to attenuated pathology of colitis when acute intestinal inflammation was induced by DSS instillation. 13 However, the precise role of TNF signaling via TNFR1 or TNFR2 during the initiation and progression of chronic intestinal inflammation remains to be elucidated.…”

Tumor-Derived GM-CSF Promotes Inflammatory Colon Carcinogenesis via Stimulating Epithelial Release of VEGF

“…Stained sections were examined for evidence of colitis according to the criteria as previously described (15). A, schematic overview of CAC regimen.…”

“…Colonic epithelial cells (CEC) were fractionated as described previously (15) with the purity >80%, identified by CK-18 staining.…”