CONSTITUTIVE CHEMOKINE PRODUCTION RESULTS IN ACTIVATION OF LEUKOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 ON ADULT T-CELL LEUKEMIA-CELLS

Adult T-cell leukemia (ATL) is characterized by massive infiltration o f circulating ATL cells into a variety of tissues, a finding often ass ociated with poor prognosis. Leukocyte migration from circulation into tissue depends on integrin-mediated adhesion to endothelium, and inte grins are tightly regulated by several stimuli, such as inflammatory c hemokines. However, the exact mechanisms that enhance adherence of leu kemic cells to the endothelium and infiltration into tissues remain to be fully understood. We investigated the mechanisms of extravasation of leukemic cells using ATL cells and report the following novel featu res of endogenous chemokine-induced adhesion of ATL cells to the endot helium. ATL cells spontaneously adhered to endothelial cells without e xogenous stimulation. Integrin leukocyte function-associated antigen-1 (LFA-1) on ATL cells was spontaneously activated, ATL cells produced high amounts of chemokines, macrophage inflammatory protein-1 alpha (M IP-1 alpha), and MIP-1 beta. Adhesion of ATL cells to endothelial cell s and the expression of activated form of LFA-1 were reduced by pretre atment with pertussis toxin, wortmannin, or anti-MIP-1 alpha and MIP-1 beta antibodies or transfection with antisense of MIP-1 alpha or MIP- 1 beta. spontaneous polymerization of cytoskeletal F-actin was observe d in ATL cells, which was also inhibited by pertussis toxin and wortma nnin. We propose that ATL cells adhere to endothelial cells through an adhesion cascade similar to normal leukocytes and that the chemokines produced by ATL cells are involved in triggering integrin LFA-1 throu gh cytoskeletal rearrangement induced by G-protein-dependent activatio n of phosphoinositide B-kinases in an autocrine manner. These events r esult in a strong adhesion of ATL cells to the endothelium and spontan eous transendothelial migration. (C) 1998 by The American Society of H ematology.