title: TACE-dependent amphiregulin release is induced by IL-1β and promotes cell invasion in fibroblast-like synoviocytes in rheumatoid arthritis.
abstract: OBJECTIVE
  The aims of this study were to investigate the expression of amphiregulin (AREG) and TNF-α-converting enzyme (TACE) in fibroblast-like synoviocytes from humans with RA (FLS-RA) when stimulated with proinflammatory cytokines and to explore whether AREG plays a role in RA.
  
  
  METHODS
  The effects of cytokines on the expression of AREG and TACE in FLS-RA were measured by quantitative RT-PCR and western blotting. Blockade of IL-1β-mediated pathways was used to verify the involvement of intracellular signal pathways in the induction of AREG and TACE. TAPI-1 and TACE short hairpin RNA (shRNA) infection were used to identify the role of TACE in IL-1β-induced AREG secretion and shedding. AREG-induced production of MMP-1 and cadherin-11 in FLS-RA were measured by ELISA or western blotting. The effect of AREG on FLS-RA invasion was examined using a Transwell invasion assay.
  
  
  RESULTS
  IL-1β, but not other tested cytokines, increased the expressions of AREG mRNA and protein in a dose-responsive and time-dependent manner in FLS-RA. IL-1β induced AREG expression via p38 MAPK, NF-κB, JNK and ERK1/2 signalling pathways and induced TACE expression via PI3K, p38MAPK and NF-κB signalling pathways in FLS-RA. TACE mediated AREG secretion and shedding. EGFR (ErbB1) and Her-2 (ErbB2) were expressed in FLS-RA, and AREG increased MMP-1 and cadherin-11 expression in FLS-RA. AREG promoted the FLS-RA invasion ability.
  
  
  CONCLUSIONS
  AREG and TACE expression were up-regulated by IL-1β and their activations on FLS-RA lead to the matrix degradation by inducing MMP-1 and cadherin-11 production. TACE activity is necessary for IL-1β-induced AREG release. Our results demonstrate that IL-1β-induced AREG release may be involved in the pathogenesis of RA.
authors.affiliation: Rheumatology/Immunology/Allergy, Tri-Service General Hospital, 325 Cheng-Kung Road, Section 2, Neihu 114, Taipei, Taiwan, Republic of China. ming0503@ms3.hinet.net.
authors.forename: Fei-Lan
authors.initials: FL
authors.lastname: Liu
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Wu
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D066258:Amphiregulin; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D066255:EGF Family of Proteins; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D015820:Cadherins; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; C086960:osteoblast cadherin; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D020781:Matrix Metalloproteinase 1; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: IL-1β; amphiregulin; fibroblast-like synoviocyte; rheumatoid arthritis