Colitogenic role of tumour necrosis factor (TNF) receptors in trinitrobenzene sulphonic acid colitis: TNF-R1 ablation does not affect systemic inflammatory response

Abstract

SummaryTumour necrosis factor (TNF)-a plays a critical role in the pathogenesis of T helper type 1-mediated colitis such as Crohn's disease. However, the roles of its two receptors in mediating pathology remain largely unknown. In this study, trinitrobenzene sulphonic acid (TNBS) was used to induce colitis in TNF-receptor single or double knock-out (DKO) BALB/c mice and in wildtype counterparts. TNF-R1 -/-mice had significantly less weight loss, reduced mortality, colon shortening and oedema, colon histological damage and lower levels of colon myeloperoxidase compared with wild-type (WT) BALB/c mice. A similar manifestation was also observed in TNF-R2-/-and TNF-R1 -/-TNF-R2-/-(TNF-R DKO) mice. Strikingly, systemic inflammatory response (including splenomegaly and monocyte expansion) was found in WT and TNF-R1 -/-mice after TNBS, instead of TNF-R2 -/-and TNF-R DKO mice. Attenuated pathology of colitis in TNF-R1-/-or TNF-R2 -/-mice correlated with lower amounts of interleukin (IL)-6, IL-1b, monocyte chemotactic protein (MCP)-1, IL-12p70 and interferon (IFN)-g production in the colons. Importantly, ablation of TNF-R1 or TNF-R2 reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick endlabelling (TUNEL)-positive apoptotic epithelial cells in the affected colons compared with WT TNBS-instilled controls, which might be due to the heightened ratio of Bcl-2/Bax and reduced activity of nuclear factor (NF)-kB. These findings suggest that either TNF-R1 or TNF-R2 plays a pathogenic role in the pathology of colitis and TNF signalling via TNF-R1 or TNF-R2 alone is not sufficient for inducing mucosal damage.

Lack of TNFRI signaling enhances annexin A1 biological activity in intestinal inflammation

“…However, clinical signs, histopathology and inflammatory biomarkers, such as MPO, returned to baseline levels in knockout earlier than in WT mice, suggesting a detrimental role for TNFR1 in the resolution of acute inflammation. In agreement, other studies demonstrated that TNFR1 ablation attenuated tissue damage after trinitrobenzene sulphonic acid (TNBS) induced colitis [35], which was related to control of NF-κB activity [36]. Yet, previous reports demonstrated that TNFR1 or TNFR2 deficiency led to exacerbation of colitis signs compared with WT counterparts [36,37] and that TNFR1-/-strain had more weight loss and increased mortality after TNBS instillation or DSS intake, respectively [37][38][39].…”

Targeted overexpression of tumor necrosis factor-α increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons

“…There was no difference in TNF-α levels between TNF-α cTg (5.5±1.0 pg/mL) and control (5.0±2.2 pg/mL) mice at 1 month of age. However, at 3 months of age the TNF-α levels increased in TNF-α cTg (14.3±1.9 pg/mL) mice as compared to controls (6.3±1.7 pg/mL) (Figure 5A) although such increased level was within the reported physiological range for TNF-α levels [66]. Nonetheless, we decided to evaluate whether this TNF-α increase deregulates the immune homeostasis.…”

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

“…In contrast, Nakai et al [11] demonstrated that TNF-R1 ablation attenuated tissue damage after TNBS, which was related to reduced NF-κB activity. Our recent study has shown that TNF signaling via TNF-R1or TNF-R2 play a pathogenic role in TNBS-induced colitis [12]. Overall, these studies underline the complexity of TNF bioactivity via TNF-R1 or 2 during the onset and perpetuation of intestinal inflammation, which may be affected by different TNF-R expression patterns and distinct colitis models used.…”

“…Interestingly, TNF signaling via TNF-R1 or 2 also appears to have distinct effects on different models of experimental colitis. Our previous study demonstrated that deficiency of TNF-R1 or 2 attenuated intestinal damage and improved the symptoms of TNBS-instilled colitis [12]. This may be explained by that different mechanisms are responsible for the initiation and progression of DSS and TNBS-induced experimental colitis respectively [24].…”