CRUCIAL ROLE OF 55-KILODALTON TNF RECEPTOR IN TNF-INDUCED ADHESION MOLECULE EXPRESSION AND LEUKOCYTE ORGAN INFILTRATION

Stimulation of leukocyte adhesion to the endothelium by TNF is mediate d by the up-regulation of adhesion molecules on the endothelial cell s urface. C57BL/6 mice and syngenic 55-kDa TNF receptor-deficient mice ( TNFRp55(-/-) mice) were challenged with TNF, and the kinetics of intra cellular adhesion molecule-1, ICAM-1, mucosal addressin cell adhesion molecule-1, vascular adhesion molecule-1 (VCAM-1), and E-selectin expr ession were examined in various organs. TNF induced sustained VCAM-1 e xpression within 4 h in lung, liver, and kidney. In the lungs, but not in other organs, transient E-selectin expression was induced by TNF w ithin 0.5 h and peaked at 4 h, The TNF-induced expression of VCAM-1 an d E-selectin was found to be exclusively controlled by the 55-kDa TNF- receptor (TNFRp55) as demonstrated by analysis of TNFRp55(-/-) mice. F urthermore, TNF triggered mononuclear cell and neutrophil infiltration of lung, liver, and kidney in C57BL/6 mice but not TNFRp55(-/-) mice. Interestingly, MAdCAM-1 expression in the marginal sinus of the splee n was detected in wild-type mice but was absent in TNFRp55(-/-) mice. Together, the data suggest that in vivo the 55-kDa TNF receptor mediat es the induction of VCAM-1 and E-selectin expression and is critically involved in the control of leukocyte organ infiltration.