Activation of monocytes by HIV-Tat treatment is mediated by cytokine expression.
Treatment of primary monocytes with soluble HIV-Tat protein is associated with increased monocyte metalloproteinase-9 (MMP-9) expression and enhanced beta 2 integrin expression that increases monocyte/endothelial adhesion. These alterations require greater than 12 h of HIV-Tat treatment, suggesting the involvement of intermediate factors. Thus, we have examined the role of cytokines in the HIV-Tat-induced alteration of monocyte function. Treatment of monocytes with HIV-Tat rapidly up-regulated the production of IL-1 beta, IL-6, IL-8, and TNF-alpha, but not IL-3, granulocyte-macrophage CSF, basic fibroblast growth factor, or macrophage-inflammatory protein-1 alpha, and was associated with up-regulation of the corresponding cytokine mRNA. Inclusion of neutralizing anti-cytokine Abs to IL-1 beta or TNF-alpha during the HIV-Tat pretreatment period significantly inhibited the HIV-Tat-induced increase in MMP-9 production, monocyte/endothelial adhesion, and monocyte-dependent endothelial damage. In contrast, neutralizing Abs against IL-6 and IL-8 had no effect. The effects of HIV-Tat treatment, namely MMP-9 production, enhanced monocyte/endothelial cell adhesion, and monocyte-dependent endothelial damage, were mimicked by treating the monocytes with IL-1 beta or TNF-alpha, but not with IL-6 or IL-8. Therefore, the mechanism by which HIV-Tat activates monocyte function is dependent on HIV-Tat-induced production of cytokines (IL-1 beta and TNF-alpha).
Lafrenie
R M
RM
Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental Research, Bethesda, MD 20892, USA.
Wahl
L M
LM
Epstein
J S
JS
Yamada
K M
KM
Dhawan
S
S
D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D017364:Collagenases / Q000096:biosynthesis / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000821:virology; D015696:Gene Products, tat / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D020780:Matrix Metalloproteinase 9; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D012333:RNA, Messenger / Q000032:analysis; D054322:tat Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; D015696:Gene Products, tat; D012333:RNA, Messenger; D054322:tat Gene Products, Human Immunodeficiency Virus; D017364:Collagenases; D020780:Matrix Metalloproteinase 9