title: Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection.
abstract: Proteinase-activated receptors (PARs), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF-alpha and IL-1beta were also increased in HIV-1-associated dementia brains compared with patients without dementia (p < 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (p < 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxicity in a mouse model of HIV neuropathogenesis (p < 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p < 0.05). TNF-alpha protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF-alpha were cytotoxic (p < 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Alberta, Canada.
authors.forename: Farshid
authors.initials: F
authors.lastname: Noorbakhsh
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.forename: Justin C
authors.initials: JC
authors.lastname: McArthur
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.forename: Mohammed
authors.initials: M
authors.lastname: Vodjgani
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
mesh_terms: D015526:AIDS Dementia Complex / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D000328:Adult; D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002474:Cell-Free System / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D005260:Female; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000633:toxicity; D005911:Gliosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D044464:Receptor, PAR-2 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020298:U937 Cells; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D016207:Cytokines; D015696:Gene Products, tat; D018836:Inflammation Mediators; D044464:Receptor, PAR-2; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D054322:tat Gene Products, Human Immunodeficiency Virus