title: HIV induces expression of complement component C3 in astrocytes by NF-κB-dependent activation of interleukin-6 synthesis.
abstract: Abnormal activation of the complement system contributes to some central nervous system diseases but the role of complement in HIV-associated neurocognitive disorder (HAND) is unclear.
  
  
  
  We used real-time PCR and immunohistochemistry to detect complement expression in postmortem brain tissue from HAND patients and controls. To further investigate the basis for viral induction of gene expression in the brain, we studied the effect of HIV on C3 expression by astrocytes, innate immune effector cells, and targets of HIV. Human fetal astrocytes (HFA) were infected with HIV in culture and cellular pathways and factors involved in signaling to C3 expression were elucidated using pharmacological pathway inhibitors, antisense RNA, promoter mutational analysis, and fluorescence microscopy.
  
  
  
  We found significantly increased expression of complement components including C3 in brain tissues from patients with HAND and C3 was identified by immunocytochemistry in astrocytes and neurons. Exposure of HFA to HIV in culture-induced C3 promoter activity, mRNA expression, and protein production. Use of pharmacological inhibitors indicated that induction of C3 expression by HIV requires NF-κB and protein kinase signaling. The relevance of NF-κB regulation to C3 induction was confirmed through detection of NF-κB translocation into nuclei and inhibition through overexpression of the physiological NF-κB inhibitor, I-κBα. C3 promoter mutation analysis revealed that the NF-κB and SP binding sites are dispensable for the induction by HIV, while the proximal IL-1β/IL-6 responsive element is essential. HIV-treated HFA secreted IL-6, exogenous IL-6 activated the C3 promoter, and anti-IL-6 antibodies blocked HIV activation of the C3 promoter. The activation of IL-6 transcription by HIV was dependent upon an NF-κB element within the IL-6 promoter.
  
  
  
  These results suggest that HIV activates C3 expression in primary astrocytes indirectly, through NF-κB-dependent induction of IL-6, which in turn activates the C3 promoter. HIV induction of C3 and IL-6 in astrocytes may contribute to HIV-mediated inflammation in the brain and cognitive dysfunction.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.|Present Address: PSI-CRO, Wisniowy Business Park C, 1 Sierpnia 6A, 02-134, Warsaw, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Nitkiewicz
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Borjabad
authors.affiliation: Manhattan HIV Brain Bank, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.affiliation: Manhattan HIV Brain Bank, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Murray
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
authors.affiliation: Department of Human and Molecular Genetics, VCU Massey Cancer Center, School of Medicine, VCU Institute of Molecular Medicine, Virginia Commonwealth UniversitySchool of Medicine, Richmond, 23298, VA, USA.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, VCU Massey Cancer Center, School of Medicine, VCU Institute of Molecular Medicine, Virginia Commonwealth UniversitySchool of Medicine, Richmond, 23298, VA, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Potash
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA. David.Volsky@mssm.edu.|Department of Medicine, Division of Infectious Diseases, 1468 Madison Avenue, Annenberg Building, 21st Floor, Room 42, New York, 10029, NY, USA. David.Volsky@mssm.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Volsky
mesh_terms: D000328:Adult; D001253:Astrocytes / Q000378:metabolism* / Q000821:virology; D002109:Caffeic Acids / Q000494:pharmacology; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015658:HIV Infections / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D002109:Caffeic Acids; D003176:Complement C3; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D016328:NF-kappa B; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: Astrocytes; Brain tissue; Complement component C3; HAND; HIV; HIV-associated dementia; IL-6; NF-κB; Neurodegeneration