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

Riadh Ksontini, MD; Sally L. D. MacKay, PhD; Lyle L. Moldawer, PhD

Arch Surg. 1998;133:558-567.

Tumor necrosis factor (TNF-) is a pleiotropic cytokine with diverse biological actions. Studies originally identified TNF- as a systemic mediator of endotoxemic shock, cachexia, and tumor regression. We now recognize that TNF- 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- inhibitors in sepsis syndrome have been disappointing to date, and TNF- administration has not proven widely successful as an antineoplastic agent, preliminary successes with TNF- inhibition have been recently reported in more chronic inflammatory diseases, including rheumatoid arthritis and ulcerative colitis. The recent description of the TNF- converting enzyme responsible for the processing of cell-associated to secreted TNF- has opened a new therapeutic avenue to address inflammatory diseases dependent on the release of 17-kd secreted TNF-. Similarly, inhibitors of nuclear factor Kappa B activation can increase TNF-–mediated apoptosis and have rejuvenated efforts to explore TNF-'s antineoplastic potential. The multiple and often conflicting TNF- signaling pathways reveal a diversity to TNF-'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- during surgical injury or acute inflammation.

From the Department of Surgery, University of Florida College of Medicine, Gainesville.

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