title: Overexpression of HDAC6 induces pro-inflammatory responses by regulating ROS-MAPK-NF-κB/AP-1 signaling pathways in macrophages.
abstract: Although histone deacetylase 6 (HDAC6) has been implicated in inflammatory diseases, direct involvement and its action mechanism of HDAC6 in the transcriptional regulation of pro-inflammatory genes have been unclear. In this study, we investigated the possible role of HDAC6 in the expression of pro-inflammatory mediators, indicator of macrophage activation, in RAW 264.7 cells and primary mouse macrophages. HDAC6 overexpression significantly enhanced expression of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, with concomitant reduction in acetylated α-tubulin. HDAC6 overexpression significantly induced ROS generation via upregulation of NADPH oxidase expression and activity. Inhibition of ROS generation by N-acetyl cysteine, diphenyl iodonium and apocynin suppressed HDAC6-induced pro-inflammatory cytokines. An HDAC6 enzymatic inhibitor significantly inhibited ROS generation and expression of HDAC6-induced pro-inflammatory mediators, indicating the requirement of HDAC6 enzymatic activity for induction of pro-inflammatory cytokines. In addition, HDAC6 overexpression increased activation of MAPK species including ERK, JNK, and p38. Furthermore, HDAC6 overexpression resulted in activation of the NF-κB and AP-1 signaling pathways. Overall, our results provide the first evidence that HDAC6 is capable of inducing expression of pro-inflammatory genes by regulating the ROS-MAPK-NF-κB/AP-1 pathways and serves as a molecular target for inflammation.
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, 1 Hallymdaehak-gil, Chunchon 200-702, Kangwon-Do, Republic of Korea.
authors.forename: Gi Soo
authors.initials: GS
authors.lastname: Youn
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, 1 Hallymdaehak-gil, Chunchon 200-702, Kangwon-Do, Republic of Korea.
authors.forename: Keun Wook
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, 1 Hallymdaehak-gil, Chunchon 200-702, Kangwon-Do, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, 1 Hallymdaehak-gil, Chunchon 200-702, Kangwon-Do, Republic of Korea. Electronic address: jinpark@hallym.ac.kr.
authors.forename: Jinseu
authors.initials: J
authors.lastname: Park
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D000073864:Histone Deacetylase 6 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D019255:NADPH Oxidases / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics*; D051996:Transcription Factor RelA / Q000235:genetics*; D014404:Tubulin / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics*
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014404:Tubulin; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6
keywords: AP-1; Cytokines; HDAC6; Inflammation; MAPK; Macrophage; NF-κB; ROS