Revisiting the Role of Tumor Necrosis Factor α and the Response to Surgical Injury and Inflammation

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Abstract
Tumor necrosis factor α (TNF-α) is a pleiotropic cytokine with diverse biological actions. Studies originally identified TNF-α as a systemic mediator of endotoxemic shock, cachexia, and tumor regression. We now recognize that TNF-α is a member of a large family of proteins, including Fas ligand, whose actions are primarily paracrine in nature, and serve to regulate both cell proliferation and apoptotic death. Although clinical trials with TNF-α inhibitors in sepsis syndrome have been disappointing to date, and TNF-α administration has not proven widely successful as an antineoplastic agent, preliminary successes with TNF-α inhibition have been recently reported in more chronic inflammatory diseases, including rheumatoid arthritis and ulcerative colitis. The recent description of the TNF-α converting enzyme responsible for the processing of cell-associated to secreted TNF-α has opened a new therapeutic avenue to address inflammatory diseases dependent on the release of 17-kd secreted TNF-α. Similarly, inhibitors of nuclear factor Kappa B activation can increase TNF-α–mediated apoptosis and have rejuvenated efforts to explore TNF-α's antineoplastic potential. The multiple and often conflicting TNF-α signaling pathways reveal a diversity to TNF-α's actions not fully appreciated in the past. Such investigations have opened a number of novel therapeutic interventions to either inhibit or potentiate the actions of TNF-α during surgical injury or acute inflammation.