Purified Tat induces inflammatory response genes in Kaposi's sarcoma cells.
OBJECTIVE
Kaposi's sarcoma (KS) is a neoplasm strongly associated with HIV-1 infection and marked by leukocytic infiltration. The infiltrating leukocytes are a possible source of inflammatory cytokines, human herpesvirus 8 (HHV8) and the HIV-1 transactivator protein Tat. This study examines whether Tat directly induces expression of cellular adhesion molecules and cytokines in KS cells and whether this induction differs in kinetics and magnitude from induction by tumour necrosis factor (TNF) alpha.


METHODS
Changes in gene expression in response to recombinant Tat compared with those to TNFalpha were evaluated at the messenger (m) RNA and protein level using cells that were cultured from KS lesions.


RESULTS
Tat induced the expression of the adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and the cytokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6). The inductions were observed at both the protein and mRNA levels. The pattern of mRNA induction over time in response to Tat differed from that to TNFalpha, with higher peak levels that occurred earlier in response to Tat. The expression of these genes is, in part, regulated by the transcription factor NF-kappaB. Tat and TNFalpha activated comparable levels of NF-kappaB.


CONCLUSIONS
The ability of the HIV-1 Tat to induce the expression of genes with kinetics that are distinct from those seen in TNFalpha induction suggests that mechanisms in addition to activation of NF-kappaB contribute to the observed induction. Tat may contribute to the pathogenesis of AIDS-related KS through induction of cellular genes that are pro-proliferative and proinflammatory and may enhance the recruitment of leukocytes, which are a possible source of further cytokines, Tat and HHV8.
Kelly
G D
GD
Winship Cancer Center, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Ensoli
B
B
Gunthel
C J
CJ
Offermann
M K
MK
D017088:AIDS-Related Opportunistic Infections / Q000235:genetics / Q000276:immunology*; D015152:Blotting, Northern; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015696:Gene Products, tat / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D016207:Cytokines; D015696:Gene Products, tat; D015850:Interleukin-6; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D054322:tat Gene Products, Human Immunodeficiency Virus; D018799:Intercellular Adhesion Molecule-1