title: Curcumin modulates the effect of histone modification on the expression of chemokines by type II alveolar epithelial cells in a rat COPD model.
abstract: BACKGROUND
  Studies have suggested that histone modification has a positive impact on various aspects associated with the progression of COPD. Histone deacetylase 2 (HDAC2) suppresses proinflammatory gene expression through deacetylation of core histones.
  
  
  OBJECTIVE
  To investigate the effect of histone modification on the expression of chemokines in type II alveolar epithelial cells (AEC II) in a rat COPD model and regulation of HDAC2 expression by curcumin in comparison with corticosteroid.
  
  
  METHODS
  The rat COPD model was established by cigarette smoke exposure and confirmed by histology and pathophysioloy. AEC II were isolated and cultured in vitro from the COPD models and control animals. The cells were treated with curcumin, corticosteroid, or trichostatin A, and messenger RNA (mRNA) expression of interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2α (MIP-2α) was assessed by quantitative real-time polymerase chain reaction (RT-PCR). The expression of HDAC2 was measured by Western blot. Chromatin immunoprecipitation was used to detect H3/H4 acetylation and H3K9 methylation in the promoter region of three kinds of chemokine genes (IL-8, MCP-1, and MIP-2α).
  
  
  RESULTS
  Compared to the control group, the mRNAs of MCP-1, IL-8, and MIP-2α were upregulated 4.48-fold, 3.14-fold, and 2.83-fold, respectively, in the AEC II from COPD model. The protein expression of HDAC2 in the AEC II from COPD model was significantly lower than from the control group (P<0.05). The decreased expression of HDAC2 was negatively correlated with the increased expression of IL-8, MCP-1, and MIP-2α mRNAs (allP<0.05). The level of H3/H4 acetylation was higher but H3K9 methylation in the promoter region of chemokine genes was lower in the cells from COPD model than from the control group (allP<0.05). Curcumin downregulated the expression of MCP-1, IL-8, and MIP-2α, and the expression was further enhanced in the presence of corticosteroid. Moreover, curcumin restored HDAC2 expression, decreased the levels of H3/H4 acetylation, and increased H3K9 methylation in the promoter region of chemokine in the presence or absence of dexamethasone (allP<0.05).
  
  
  CONCLUSIONS
  Curcumin may suppress chemokines and restore corticosteroid resistance in COPD through modulating HDAC2 expression and its effect on histone modification.
authors.affiliation: Department of Respiratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai.
authors.forename: Lixing
authors.initials: L
authors.lastname: Gan
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou.
authors.forename: Chengye
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Guo
mesh_terms: D000107:Acetylation; D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008745:Methylation; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; C513296:Cxcl2 protein, rat; D006657:Histones; D016209:Interleukin-8; D012333:RNA, Messenger; D012906:Smoke; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2; D003474:Curcumin
keywords: chronic obstructive pulmonary disease; corticosteroid; curcumin; histone deacetylase; type II alveolar epithelial cell