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Effect of Genetic Deletion or Pharmacological Antagonism of Tumor Necrosis Factor Alpha on Colitis-associated Carcinogenesis in Mice

Background:Intestinal inflammation in inflammatory bowel diseases is driven by abnormal levels of proinflammatory cytokines, where tumor necrosis factor (TNF)-&agr; seems to be particularly important. Chronic inflammatory signaling in the colon increases the risk of colorectal cancer, so we sought to evaluate the role of TNF-&agr; in a mouse model of this condition. Methods:TNF−/− mice were treated with azoxymethane/dextran sulfate sodium to induce inflammation and tumorigenesis. Etanercept was used to produce pharmacological ablation of TNF-&agr; in wild-type mice. Subsequent activation of procarcinogenic transcription factor NF-&kgr;B and relevant proinflammatory cytokines of the TNF superfamily were measured through immunohistochemistry and quantitative polymerase chain reaction methods. Results:Results showed that the severity of colitis, as assessed by mortality, histological scoring, and cytokine expression levels, was similar or slightly higher in mice lacking TNF-&agr; than in control mice. Activation levels of NF-&kgr;B were not influenced by the presence of TNF-&agr;. We also observed upregulated expression of TNF family member TNF-&bgr;, TNF receptors 1 and 2 and a variety of other proinflammatory factors in colitis-associated tumors of TNF−/− mice, compared with levels in tumors of control mice. Neither genetic ablation of TNF-&agr; nor pharmacological inhibition of the TNF family using etanercept reduced tumor number. Conclusions:Our results reveal a redundant role for TNF-&agr; in a mouse model of colitis-associated tumorigenesis, indicating a high degree of redundancy in proinflammatory cytokine networks in this model.