title: Interleukin-29 induces receptor activator of NF-κB ligand expression in fibroblast-like synoviocytes via MAPK signaling pathways.
abstract: OBJECTIVE
  We previously reported that interleukin-29 (IL-29) was highly expressed in the blood and synovium of rheumatoid arthritis (RA) patients and contributed to synovial inflammation by induction of proinflammatory cytokine production. Given chronic inflammation can trigger the process of bone erosion, and receptor activator of nuclear factor-κB ligand (RANKL) plays a crucial role in bone erosion of RA, we hypothesize that IL-29 mediates bone erosion in RA by regulation of RANKL expression. Here, we investigated the effect of IL-29 on RANKL expression in RA fibroblast-like synoviocytes (FLS) and the relevant signaling pathways involved in it.
  
  
  METHODS
  Primary fibroblast cells isolated from RA patients were stimulated by recombinant IL-29 in the presence or absence of anti-IL-29 antibody, and the expression levels of RANKL were assessed using real-time polymerase chain reaction and immunostaining. Furthermore, the IL-29 signaling pathway for regulation of RANKL was also examined by Western blotting assay.
  
  
  RESULTS
  IL-29 upregulated RANKL expression in a dose-dependent manner, and blockade of IL-29 resulted in a significantly reduced RANKL expression in RA-FLS. Incubation RA-FLS with IL-29 (100 ng/mL) led to phosphorylation of ERK (extracellular signal-regulated kinase), p38 and JNK (c-Jun N-terminal kinase). The expression of RANKL induced by IL-29 could be completely blocked by the inhibitors of mitogen-activated protein kinase (MAPK) signal pathway, including PD98059 (ERK inhibitor), SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor).
  
  
  CONCLUSIONS
  These findings indicate, for the first time, that IL-29 could directly induce RANKL expression in RA-FLS via MAPK signaling pathway, suggesting IL-29 might be a new target in the prevention of joint destruction in RA.
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Traditional Chinese Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yumeng
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Traditional Chinese Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Miaojia
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation; D000095022:Interferon Lambda
chemical_list: D057134:Antibodies, Neutralizing; D007372:Interferons; D007378:Interleukins; D020928:Mitogen-Activated Protein Kinases; D047428:Protein Kinase Inhibitors; D053245:RANK Ligand; D011994:Recombinant Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C505688:TNFSF11 protein, human
keywords: inflammation; interleukin-29; mitogen-activated protein kinase; osteoclastogenesis; receptor activator of nuclear factor κB ligand; synoviocytes