Transmembrane tumor necrosis factor is a potent inducer of colitis even in the absence of its secreted form (original) (raw)
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Lack of TNFR2 expression by CD4 + T cells exacerbates experimental colitis
European Journal of Immunology, 2009
TNF plays fundamental roles in the induction and perpetuation of inflammation. The effects of TNF are mediated through TNF receptor (TNFR) 1 or 2. As these two receptors mediate different functions, selective targeting of one receptor may represent a more specific treatment for inflammatory disorders than the complete blocking of TNF. TNFR2 expression is up-regulated in inflammatory bowel disease. Hence, we directly assessed the role of TNFR2 signaling in the CD4 + T-cell transfer model of colitis using TNFR2 À/À or WT mice as donors of colitogenic CD4 + CD45RB hi T cells for transfer into syngeneic RAG2 À/À or RAG2 À/À TNFR2 À/À recipient mice. Although the absence of TNFR2 expression by nonlymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2 À/À CD4 + T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2 À/À CD4 1 T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2 À/À CD4 1 T cells. Hence, TNFR2 signaling is crucial for the TNF-dependent contraction of the disease-inducing T cells. Therefore, a selective blocking of TNFR2 may lead to exacerbation rather than attenuation of T-cell-mediated inflammatory disorders.
Journal of Experimental Medicine, 1999
In this study, we addressed the role of tumor necrosis factor (TNF)-α and lymphotoxin (LT)-α in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF-α and LT-α) relevant to disease development. After adoptive transfer of TNF+/+ CD4+CD45RBhi splenocytes into TNF+/+ recombination activating gene (RAG)2−/− mice, the recipients develop massive inflammation of the large intestinal mucosa concurrent with massive weight loss. In contrast, clinical signs of disease are completely absent in TNF−/−RAG2−/− recipients of TNF−/− CD4+CD45RBhi T cells, although elevated numbers of interferon-γ–producing cells are present in the colonic mucosa. Surprisingly, upon transfer of TNF−/−CD4+CD45RBhi T cells into TNF+/+RAG2−/− recipients, colitis develops with kinetics similar to those upon transfer of TNF+/+CD4+CD45RBhi donor cells. In contrast, no clinical signs of colitis are observed in TNF−/−RAG2−/− recipients of TNF+/+CD4+CD45RBhi T cells. This protect...
Clinical and Experimental Immunology, 1999
The adoptive transfer of activated CD4 þ a/b T cell blasts from the spleens of immunocompetent C.B-17 þ/þ or BALB/c dm2 mice into C.B-17 scid/scid (scid) mice induces a colitis in the scid recipient within 8 weeks, which progresses to severe disease within 16 weeks. T cells isolated from recipient colon show a Th1 cytokine phenotype. We have examined the relationship between the phenotype of the cellular infiltrate and the transcription and translation of the proinflammatory cytokine TNF-a. The techniques of double indirect immunohistology and in situ hybridization using digoxigenin-labelled riboprobes were used. The prominent myeloid cell infiltrate in diseased tissues comprised F4/80 þ , Mac-l þ macrophages, neutrophils, dendritic cells and activated macrophages. TNF-a transcription and translation were associated with activated macrophages in the lamina propria. Activated macrophages transcribing and translating TNF-a were clustered in areas of tissue destruction. Crypt epithelium of inflamed tissues transcribed TNF-a at a very early stage of the disease process, but translation of TNF-a protein could only be found in advanced epithelial dysplasia. This indicates differential post-transcriptional control of TNF-a in activated macrophages and the epithelium.
Systemic tumor necrosis factor-alpha production in experimental colitis
Digestive Diseases and Sciences, 1992
Tumor necrosis factor-alpha (TNF) is a cytokine released by mononuclear cells in response to inflammation and sepsis. Since the biological effects of TNF are consistent with the systemic and intestinal features of ulcerative colitis, the role of TNF was examined in a rabbit model of chronic colitis. Peripheral blood mononuclear cells were isolated, stimulated with lipopolysaccharide, and cultured supernatants assayed for TNF levels using a cytotoxic assay on mouse fibrosarcoma L929 cells. Basal levels of TNF production by mononuclear cells from 13 normal rabbits (124.3 units/ml +-27.1 units/ml, mean +-SE) were not different from nine rabbits with colitis (83.6 units/ml +-24.4 units/ml, P > 0.05). Treatment with lipopolysaccharide (100 Ixg/ml) induced increased TNF production by mononuclear cells isolated from both normals (672.0 units/ml +-197.5 units/ml, P < 0.05) and rabbits with colitis (1114.0 units/ml +-489.6 units/ml, P < 0.05). However, at all lipopolysaccharide concentrations stimulated TNF levels were comparable in experimental and control groups (P > 0.05). In light of the role of leukotrienes in inflammation, a separate group of rabbits with colitis was investigated following treatment with an oral leukotriene B 4 receptor antagonist. Serum TNF levels in 15 control rabbits (32.5 units/ml +-7.6 units/ml, mean +-SE) were not significantly different from rabbits with colitis receiving either leukotriene B 4 receptor antagonist (35.7 units/ml +-9.2 units/ml, N= 13) or vehicle alone (50.3 units/ml +-10.2 units/ml, N = 14) (ANOVA, P > 0.05). These data indicate that systemic levels of TNF are not elevated in this experimental model of chronic colitis. Therefore, other inflammatory mediators with biological functions parallel to those of TNF are likely to mediate the systemic manifestations of colitis.
Role of tumor necrosis factor receptors in an animal model of acute colitis
Cytokine, 2005
TNF-alpha is known to play an important role in inflammatory bowel disease (IBD); however, the pathophysiological role of its receptors is still under study. Acute colitis was induced in rats by intracolonic administration of trinitrobenzene sulfonic acid (TNBS). Control rats received the ethanol vehicle. Rats were sacrificed 72 h later and samples of tissue and fluids were collected. There was a significant increase in the protein levels of sTNF-alpha, sTNFRI, and sTNFRII in the peritoneal fluid (PF) of experimental rats. TNF-alpha, TNFRI, and TNFRII mRNA expression was increased significantly in the colon of experimental animals compared to controls. TRAF3 and TRAF5 expression was also significantly higher, as was that of the adhesion molecules ICAM-1 and E-selectin. The increased expression of TNF-alpha, TNFRs, and the associated signaling factors in the colon of this rat model of IBD provides further evidence for their involvement in the promotion of inflammation and tissue dama...
Treatment of experimental colitis in mice with LMP-420, an inhibitor of TNF transcription
Journal of Inflammation, 2008
Background: LMP-420 is a boronic acid-containing purine nucleoside analogue that transcriptionally inhibits TNF production but is non-cytotoxic to TNF-producing cells. Methods: This study investigated the efficacy of LMP-420 as an anti-inflammatory agent in acute and chronic colitis induced by oral administration of dextran sulfate sodium (DSS) to mice and in chronic colitis following piroxicam administration to IL-10-deficient mice. The severity of colon inflammation was assessed histologically. TNF levels were measured by enzyme immunoassay. Results: Administration of DSS for 7 days resulted in severe acute colitis that was associated with a marked increase in stool and colon tissue TNF levels. Initiation of therapy with intraperitoneal (i.p.) LMP-420 on day 4 of DSS exposure decreased colonic TNF to near normal levels on day 7. However, neither i.p. nor oral treatment with LMP-420 affected the development or severity of acute DSS colitis. Initiation of LMP-420 therapy after 3 cycles of DSS administration to establish chronic colitis also had no effect on the severity of chronic colitis. Analysis of colonic TNF combined with longitudinal analysis of TNF and TNF receptor (TNF-RII) levels in stool during the development of chronic DSS colitis demonstrated that the initially elevated colonic TNF levels returned to normal despite intense ongoing inflammation in mice with chronic colitis. RAG-2-/mice deficient in T and B cells also developed severe ongoing colitis in response to 3 cycles of DSS, but showed marked differences vs. wild type mice in stool TNF and TNF-RII in response to DSS exposure. Systemic and oral LMP-420 treatment for 16 days decreased colonic TNF levels in IL-10-deficient mice with chronic colitis, with a trend to decreased histologic inflammation for oral LMP-420. Conclusion: These studies demonstrate that short-term treatment with a transcriptional inhibitor of TNF production can decrease systemic and local colonic levels of TNF but may not decrease the histologic severity of colitis. Longer term studies using colitis models that are more dependent on TNF elevation should be performed to more accurately assess the potential of LMP-420 for therapy of inflammatory bowel disease.