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Science 13 March 1992:
Vol. 255. no. 5050, pp. 1427 - 1430
DOI: 10.1126/science.1371890
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Articles

Science, Vol 255, Issue 5050, 1427-1430
Copyright © 1992 by American Association for the Advancement of Science

articles

Formation of ion-permeable channels by tumor necrosis factor-alpha

BL Kagan, RL Baldwin, D Munoz, and BJ Wisnieski

Department of Psychiatry, School of Medicine, University of California, Los Angeles 90024.

Tumor necrosis factor-alpha (TNF, cachectin), a protein secreted by activated macrophages, participates in inflammatory responses and in infectious and neoplastic disease states. The mechanisms by which TNF exerts cytotoxic, hormonal, and other specific effects are obscure. Structural studies of the TNF trimer have revealed a central pore-like region. Although several amino acid side chains appear to preclude an open channel, the ability of TNF to insert into lipid vesicles raised the possibility that opening might occur in a bilayer milieu. Acidification of TNF promoted conformational changes concordant with increased surface hydrophobicity and membrane insertion. Furthermore, TNF formed pH-dependent, voltage-dependent, ion-permeable channels in planar lipid bilayer membranes and increased the sodium permeability of human U937 histiocytic lymphoma cells. Thus, some of the physiological effects of TNF may be elicited through its intrinsic ion channel-forming activity.


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