Involvement of cytokines in human immunodeficiency virus-1 protein Tat and methamphetamine interactions in the striatum.
Human immunodeficiency virus-1 (HIV-1) infection of the brain causes elevation in pro-inflammatory cytokines and inflammatory changes in the striatum. HIV-1-infected individuals who also abuse drugs including the psychostimulant methamphetamine (MA) develop more severe encephalitis and neuronal damage compared to HIV-1-infected patients who do not abuse drugs. In previous studies, we demonstrated that the HIV-1 protein Tat and MA interacted to cause enhanced loss of dopamine in the rat striatum via the destruction of dopaminergic terminals. Since both Tat and MA activate glia and induce cytokine production, we investigated the role of cytokines in the synergistic neurotoxicity induced by Tat and MA using cytokine arrays. Significant increases in monocyte chemotactic protein (MCP-1), interleukin-1 alpha (IL-1alpha) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were noted 4 h following Tat + MA treatment compared to saline, Tat or MA. MCP-1 and TIMP-1 levels remained elevated 16 h after Tat + MA compared to saline or MA but were not different from the Tat-treated group at this time point. Weak, but significant elevations in cytokine-induced neutrophil chemoattractant-3 (CINC-3), ciliary neurotrophic factor (CNTF) and macrophage inflammatory protein-3 alpha (MIP-3alpha) were also noted with Tat + MA. The interaction of Tat and MA was prevented in mice genetically deficient in MCP-1 with a consequent attenuation of Tat + MA neurotoxicity. Our findings suggest that HIV-1 infection with concurrent drug abuse might profoundly increase chemokine levels in the striatum resulting in enhanced damage to the dopaminergic system.
Theodore
Shaji
S
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Cass
Wayne A
WA
Maragos
William F
WF
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D016207:Cytokines / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000502:physiology; D015696:Gene Products, tat / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000737:chemistry* / Q000472:pathogenicity; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D054322:tat Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; D018765:Dopamine Uptake Inhibitors; D015696:Gene Products, tat; D005904:Glial Fibrillary Acidic Protein; D054322:tat Gene Products, Human Immunodeficiency Virus; D008694:Methamphetamine