L-SELECTIN MEDIATES DOWN-REGULATION OF NEUTROPHIL TNF RECEPTORS

Tumor necrosis factor (TNF) is a potent activator of neutrophil granul ocytes, which acts via two cell-surface receptors: the p55-TNF recepto r (TNF-R55) and the p75TNF receptor (TNF-R75). Proteolytic cleavage of the extracellular region of the receptors results in formation of sol uble TNF-binding proteins, TNF-R55-BP and TNP-R75-BP. We recently repo rted that adherence alone, without any further stimuli, causes release of both TNF-R55-BP and TNF-R75-BP and that both leukocyte-integrin-de pendent and non-integrin-dependent adherence mechanisms can modulate T NF receptor expression. In the present work we show that crosslinking of a mAb to the adhesion protein L-selectin (TQ1) on the surface of ne utrophils results in downregulation of TNF-receptor binding capacity. Furthermore, when the fluctuations of cytosolic free calcium found in adherent neutrophils were blocked with the cell-permeable calcium chel ator BAPTA, adherence-induced release of TNF-R55-BP was inhibited. We have shown that adherence, via mechanisms involving two adhesion prote ins, L-selectin and the CD11/CD18 leukocyte integrins, and fluctuation s of cytosolic free calcium, can result in downregulation of neutrophi l TNF-receptors.