HIV induces expression of complement component C3 in astrocytes by NF-κB-dependent activation of interleukin-6 synthesis
| Autor: | Mary Jane Potash, Paul B. Fisher, Wei Chao, Jadwiga Nitkiewicz, Luni Emdad, David J. Volsky, Jacinta Murray, Alejandra Borjabad, Susan Morgello |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male HIV Infections NF-κB chemistry.chemical_compound 0302 clinical medicine Transcription (biology) Gene expression Enzyme Inhibitors Promoter Regions Genetic HIV-associated dementia Effector General Neuroscience Neurodegeneration NF-kappa B Complement C3 Middle Aged Phenylethyl Alcohol Brain tissue 3. Good health Cell biology Neurology Female Signal Transduction Adult Gene Expression Regulation Viral Complement component C3 Immunology Enzyme Activators Biology HAND 03 medical and health sciences Cellular and Molecular Neuroscience Caffeic Acids Fetus Glial Fibrillary Acidic Protein medicine Humans Protein kinase A IL-6 Innate immune system Interleukin-6 Research HIV medicine.disease Complement system Enzyme Activation 030104 developmental biology chemistry Gene Expression Regulation Astrocytes 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuroinflammation |
| ISSN: | 1742-2094 |
| Popis: | Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (doi:10.1186/s12974-017-0794-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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