title: 15-deoxy-Δ¹²,¹⁴ -prostaglandin J₂ inhibits human immunodeficiency virus-1 tat-induced monocyte chemoattractant protein-1/CCL2 production by blocking the extracellular signal-regulated kinase-1/2 signaling pathway independently of peroxisome proliferator-activated receptor-γ and heme oxygenase-1 in rat hippocampal slices.
abstract: Human immunodeficiency virus (HIV)-induced inflammation, and its consequences within the central nervous system (CNS), must be countered by multiple pharmacologic agents, and 15-deoxy-Δ(12,14) -prostaglandin J(2) (15d-PGJ2) may hold promise in the treatment of pathologies associated with this inflammatory response. 15d-PGJ2 can repress the inflammatory response by means of peroxisome proliferator-activated receptor-γ (PPARγ)-dependent and -independent mechanisms. However, its precise role and antiinflammatory mechanism in the hippocampus remain poorly understood. In the present study, rat hippocampal slices were stimulated with full-length HIV-1 Tat protein to investigate the role of 15d-PGJ2 8in the hippocampal inflammatory response. Pretreatment of slices with 15d-PGJ2 markedly reduced Tat-induced monocyte chemoattractant protein-1 (MCP-1/CCL2) production. Interestingly, the PPARγ antagonist GW9662 did not inhibit action of 15d-PGJ2, confirming the latter's PPARγ-independent mechanism of mediating antiinflammatory effects. Despite 15d-PGJ2's increasing the expression of heme oxygenase-1 (HO-1), its action was not abrogated by the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), nor was it recapitulated by HO-1 inducers such as cobalt protoporphyrin (CoPP). Moreover, short interfering RNA (siRNA)-directed knockdown of HO-1 did not abolish the antiinflammatory action of 15d-PGJ2 against Tat-induced MCP-1 production in human microglia-like THP-1 cells. Conversely, 15d-PGJ2 suppressed Tat-induced ERK1/2 activation, decreasing MCP-1 production upon Tat stimulation. The NADPH oxidase inhibitors DPI and apocynin also abrogated Tat-stimulated ERK1/2 activation, reducing MCP-1 production. Collectively, these data demonstrate that the antiinflammatory effects of 15d-PGJ2 on the hippocampus are exerted through inhibition of Tat-mediated ERK1/2 activation, coupled with that of a redox-sensitive pathway, independent of PPARγ and HO-1.
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Medical Research Institute, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Eun Ok
authors.initials: EO
authors.lastname: Lee
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Yang
authors.forename: Ji Hee Lee
authors.initials: JH
authors.lastname: Kang
authors.forename: Yoo-Hun
authors.initials: YH
authors.lastname: Suh
authors.forename: Young Hae
authors.initials: YH
authors.lastname: Chong
mesh_terms: D000818:Animals; D051381:Rats; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: C477819:15-deoxyprostaglandin J2; D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D051547:Heme Oxygenase-1; D047495:PPAR gamma; D015230:Prostaglandin D2; D054322:tat Gene Products, Human Immunodeficiency Virus