Revisiting the role of tumor necrosis factor alpha and the response to surgical injury and inflammation.
Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine with diverse biological actions. Studies originally identified TNF-alpha as a systemic mediator of endotoxemic shock, cachexia, and tumor regression. We now recognize that TNF-alpha 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-alpha inhibitors in sepsis syndrome have been disappointing to date, and TNF-alpha administration has not proven widely successful as an antineoplastic agent, preliminary successes with TNF-alpha inhibition have been recently reported in more chronic inflammatory diseases, including rheumatoid arthritis and ulcerative colitis. The recent description of the TNF-alpha converting enzyme responsible for the processing of cell-associated to secreted TNF-alpha has opened a new therapeutic avenue to address inflammatory diseases dependent on the release of 17-kd secreted TNF-alpha. Similarly, inhibitors of nuclear factor kappa B activation can increase TNF-alpha-mediated apoptosis and have rejuvenated efforts to explore TNF-alpha's antineoplastic potential. The multiple and often conflicting TNF-alpha signaling pathways reveal a diversity to TNF-alpha'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-alpha during surgical injury or acute inflammation.
Ksontini
R
R
Department of Surgery, University of Florida College of Medicine, Gainesville 32610, USA.
MacKay
S L
SL
Moldawer
L L
LL
D017209:Apoptosis; D006801:Humans; D007249:Inflammation; D007431:Intraoperative Complications / Q000378:metabolism* / Q000628:therapy; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha