title: Role of macrophage CCAAT/enhancer binding protein delta in the pathogenesis of rheumatoid arthritis in collagen-induced arthritic mice.
abstract: BACKGROUND
  The up-regulation of CCAAT/enhancer binding protein delta (CEBPD) has frequently been observed in macrophages in age-associated disorders, including rheumatoid arthritis (RA). However, the role of macrophage CEBPD in the pathogenesis of RA is unclear.
  
  
  RESULTS
  We found that the collagen-induced arthritis (CIA) score and the number of affected paws in Cebpd(-/-) mice were significantly decreased compared with the wild-type (WT) mice. The histological analysis revealed an attenuated CIA in Cebpd(-/-) mice, as shown by reduced pannus formation and greater integrity of joint architecture in affected paws of Cebpd(-/-) mice compared with WT mice. In addition, immunohistochemistry analysis revealed decreased pannus proliferation and angiogenesis in Cebpd(-/-) mice compared with WT mice. CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. CCL20, IL23A, CXCL1 and TNFAIP6 contributed to the migration and proliferation of synoviocytes, and the latter two proteins were involved in tube formation of endothelial cells. Finally, two anti-inflammatory chemicals, inotilone and rosmanol, reduced the expression of CEBPD and its downstream targets and mitigated the above phenomena.
  
  
  CONCLUSIONS
  Collectively, our findings suggest that CEBPD and its downstream effectors could be biomarkers for the diagnosis of RA and potentially serve as therapeutic targets for RA therapy.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, Tainan, Taiwan.
authors.forename: Ling-Hua
authors.initials: LH
authors.lastname: Chang
authors.forename: Huei-Sheng
authors.initials: HS
authors.lastname: Huang
authors.forename: Po-Ting
authors.initials: PT
authors.lastname: Wu
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Jou
authors.forename: Min-Hsiung
authors.initials: MH
authors.lastname: Pan
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.forename: Dennis Ding Hwa
authors.initials: DD
authors.lastname: Wang
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D006801:Humans; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D015815:Cell Adhesion Molecules; D054418:Chemokine CCL20; D054360:Chemokine CXCL1; C508841:Il23a protein, mouse; D053760:Interleukin-23 Subunit p19; C513057:Tnfaip6 protein, mouse; D051743:CCAAT-Enhancer-Binding Protein-delta