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 of circulating ATL cells into a variety of tissues, a finding often associated with poor prognosis. Leukocyte migration from circulation into tissue depends on integrin-mediated adhesion to endothelium, and integrins are tightly regulated by several stimuli, such as inflammatory chemokines. However, the exact mechanisms that enhance adherence of leukemic 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 features of endogenous chemokine-induced adhesion of ATL cells to the endothelium. ATL cells spontaneously adhered to endothelial cells without exogenous 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-1alpha (MIP-1alpha), and MIP-1beta. Adhesion of ATL cells to endothelial cells and the expression of activated form of LFA-1 were reduced by pretreatment with pertussis toxin, wortmannin, or anti-MIP-1alpha and MIP-1beta antibodies or transfection with antisense of MIP-1alpha or MIP-1beta. Spontaneous polymerization of cytoskeletal F-actin was observed in ATL cells, which was also inhibited by pertussis toxin and wortmannin. 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 through cytoskeletal rearrangement induced by G-protein-dependent activation of phosphoinositide 3-kinases in an autocrine manner. These events result in a strong adhesion of ATL cells to the endothelium and spontaneous transendothelial migration.
Tanaka
Y
Y
The First Department of Internal Medicine , University of Occupational and Environmental Health, Japan.
Mine
S
S
Figdor
C G
CG
Wake
A
A
Hirano
H
H
Tsukada
J
J
Aso
M
M
Fujii
K
K
Saito
K
K
van Kooyk
Y
Y
Eto
S
S
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000199:Actins / Q000378:metabolism; D000328:Adult; D000730:Androstadienes / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016373:DNA, Antisense / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D037342:Pertussis Toxin; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014471:Umbilical Veins; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000077191:Wortmannin
D000199:Actins; D000730:Androstadienes; D000911:Antibodies, Monoclonal; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016373:DNA, Antisense; D016169:Lymphocyte Function-Associated Antigen-1; D019402:Macrophage Inflammatory Proteins; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019204:GTP-Binding Proteins; D000077191:Wortmannin