title: Toll-like receptor expression and activation in astroglia: differential regulation by HIV-1 Tat, gp120, and morphine.
abstract: In this study, we aimed to determine whether morphine alone or in combination with HIV-1 Tat or gp120 affects the expression of Toll-like receptors (TLRs) by astrocytes and to assess whether TLRs expressed by astrocytes function in the release of inflammatory mediators in vitro. TLR profiling by immunofluorescence microscopy, flow cytometry, in-cell westerns, and RT-PCR showed that subpopulations of astrocytes possessed TLR 2, TLR3, TLR4, and TLR9 antigenicity. Exposure to HIV-1 Tat, gp120, and/or morphine significantly altered the proportion of TLR-immunopositive and/or TLR expression by astroglia in a TLR-specific manner. Subsets of astroglia displayed significant increases in TLR2 with reciprocal decreases in TLR9 expression in response to Tat or gp120 ± morphine treatment. TLR9 expression was also significantly decreased by morphine alone. Exposing astrocytes to the TLR agonists LTA (TLR2), poly I:C (TLR3), LPS (TLR4) and unmethylated CpG ODN (TLR9) resulted in increased secretion of MCP-1/CCL2 and elevations in reactive oxygen species. TLR3 and TLR4 stimulation increased the secretion of TNF-α, IL-6, and RANTES/CCL5, while activation of TLR2 caused a significant increase in nitric oxide levels. The results suggest that HIV-1 proteins and/or opioid abuse disrupt the innate immune response of the central nervous system (CNS) which may lead to increased pathogenicity.
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, USA. nelhage@vcu.edu
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Podhaizer
authors.forename: Jamie
authors.initials: J
authors.lastname: Sturgill
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D015699:HIV Envelope Protein gp120; D009294:Narcotics; D009573:Nitrites; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D054322:tat Gene Products, Human Immunodeficiency Virus; D009020:Morphine