Human immunodeficiency virus transactivator protein (Tat) stimulates chemotaxis, calcium mobilization, and activation of human polymorphonuclear leukocytes: implications for Tat-mediated pathogenesis.
The extracellular activities of the human immunodeficiency virus (HIV) transactivator protein (Tat) include induction of angiogenesis and stimulation of monocyte migration. Here it is shown that polymorphonuclear leukocytes (PMNL), mostly neutrophils, rapidly invade in response to Tat in vivo and initiate the formation of new vessels. In vitro, Tat was chemotactic for PMNL and induced calcium (Ca(2+)) mobilization. Tat proteins with inactivating substitutions in the arginine-glycine-aspartic acid or basic domain were still active in inducing PMNL migration, whereas Tat peptides mapped the migration and Ca(2+) mobilization activity to a cysteine-rich core domain, previously described as a Tat "chemokine-like" region (peptide CysL(24-51)). Tat and the CysL(24-51) peptide also induced PMNL superoxide production and the release of the angiogenic factors interleukin-8 and vascular endothelial growth factor from PMNL. CysL(24-51) did not induce endothelial cell migration but was angiogenic in vivo. These data indicate that the Tat activity on PMNL is mediated by its chemokine-like region and that PMNL recruitment by Tat is linked to angiogenesis.
Benelli
R
R
Tumor Progression Section, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Barbero
A
A
Ferrini
S
S
Scapini
P
P
Cassatella
M
M
Bussolino
F
F
Tacchetti
C
C
Noonan
D M
DM
Albini
A
A
D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000032:analysis / Q000378:metabolism; D015696:Gene Products, tat / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D005998:Glycine / Q000235:genetics; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis / Q000378:metabolism; D007797:Laminin; D008222:Lymphokines / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000209:etiology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011509:Proteoglycans; D011994:Recombinant Proteins / Q000096:biosynthesis; D013481:Superoxides / Q000032:analysis / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004338:Drug Combinations; D016228:Endothelial Growth Factors; D015696:Gene Products, tat; D016209:Interleukin-8; D007797:Laminin; D008222:Lymphokines; D011509:Proteoglycans; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013481:Superoxides; C059485:matrigel; D001224:Aspartic Acid; D003094:Collagen; D001120:Arginine; D002118:Calcium; D005998:Glycine