HDAC6 mediates HIV-1 tat-induced proinflammatory responses by regulating MAPK-NF-kappaB/AP-1 pathways in astrocytes

• Published in: Glia Vol. 63; no. 11; pp. 1953 - 1965
• Main Authors: Youn, Gi Soo, Ju, Sung Mi, Choi, Soo Young, Park, Jinseu
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2015; Wiley Subscription Services, Inc
• Subjects: astrocyte; Chemokines; HDAC6; HIV-1 Tat; Human immunodeficiency virus; Human immunodeficiency virus 1; inflammation; Kinases; MAPK; NF-κB; Proteins; Rodents; NF-κB; HIV-1 Tat; MAPK; inflammation; astrocyte; HDAC6
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22865

Human immunodeficiency virus (HIV)‐1 transactivator of transcription (Tat) is a viral protein that induces extensive neuroinflammation by up‐regulating proinflammatory mediators, including cytokines, chemokines, and adhesion molecules. Histone deacetylase 6 (HDAC6) has been implicated in the transcriptional regulation of inflammatory genes. In this study, we investigated the possible role of HDAC6 in HIV‐1 Tat‐induced up‐regulation of proinflammatory mediators in astrocytes. HIV‐1 Tat augmented HDAC6 expression, which was correlated with a reduction in acetylated α‐tubulin in CRT‐MG human astroglioma cells and primary mouse astrocytes. Knockdown and pharmacological inhibition of HDAC6 significantly inhibited HIV‐1 Tat‐induced expression of CCL2, CXCL8, and CXCL10 chemokines; adhesion molecules; and subsequent adhesion of monocytes to astrocytes. HDAC6 knockdown attenuated HIV‐1 Tat‐induced activation of mitogen‐activated protein kinase species, including ERK, JNK, and p38. Furthermore, HDAC6 knockdown suppressed HIV‐1 Tat‐induced activation of NF‐κB and AP‐1. Thus, HDAC6 is involved in HIV‐1 Tat‐induced expression of proinflammatory genes by regulating mitogen‐activated protein kinase‐NF‐κB/AP‐1 pathways and serves as a molecular target for HIV‐1 Tat‐mediated neuroinflammation GLIA 2015;63:1953–1965 Main Points HIV‐1 Tat increases HDAC6 expression in astrocytes. HDAC6 is involved in HIV‐1 Tat‐induced expression of chemokines and adhesion molecules. HDAC6 mediates HIV‐1 Tat‐induced activation of MAP kinases and NF‐κB/AP‐1 signaling pathways.