title: Heterogeneous requirement of IkappaB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: implications for therapy.
abstract: OBJECTIVE
  To investigate the potential role of IkappaB kinase 1 (IKK-1) and IKK-2 in the regulation of nuclear factor kappaB (NF-kappaB) activation and the expression of tumor necrosis factor alpha (TNFalpha), as well as interleukin-1beta (IL-1beta), IL-6, IL-8, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), in rheumatoid arthritis (RA).
  
  
  METHODS
  Recombinant adenoviruses expressing beta-galactosidase, dominant-negative IKK-1 and IKK-2, or IkappaBalpha were used to infect ex vivo RA synovial membrane cultures and synovial fibroblasts obtained from patients with RA undergoing joint replacement surgery, or human dermal fibroblasts, human umbilical vein endothelial cells (HUVECs), and monocyte-derived macrophages from healthy volunteers. Then, their effect on the spontaneous or stimulus-induced release of inflammatory cytokines, VEGF, and MMPs from RA synovial membrane cells was examined.
  
  
  RESULTS
  IKK-2 was not required for lipopolysaccharide (LPS)-induced NF-kappaB activation or TNFalpha, IL-6, or IL-8 production in macrophages, but was essential for this process in response to CD40 ligand, TNFalpha, and IL-1. In synovial fibroblasts, dermal fibroblasts, and HUVECs, IKK-2 was also required for LPS-induced NF-kappaB activation and IL-6 or IL-8 production. In RA synovial membrane cells, IKK-2 inhibition had no effect on spontaneous TNFalpha production but significantly reduced IL-1beta, IL-6, IL-8, VEGF, and MMPs 1, 2, 3, and 13.
  
  
  CONCLUSIONS
  Our study demonstrates that IKK-2 is not essential for TNFalpha production in RA. However, because IKK-2 regulates the expression of other inflammatory cytokines (IL-1beta, IL-6, and IL-8), VEGF, and MMPs 1, 2, 3, and 13, which are involved in the inflammatory, angiogenic, and destructive processes in the RA joint, it may still be a good therapeutic target.
authors.affiliation: Kennedy Institute of Rheumatology, Imperial College of Science, Technology and Medicine, London, UK.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Andreakos
authors.forename: Clive
authors.initials: C
authors.lastname: Smith
authors.forename: Serafim
authors.initials: S
authors.lastname: Kiriakidis
authors.forename: Claudia
authors.initials: C
authors.lastname: Monaco
authors.forename: Rainer
authors.initials: R
authors.lastname: de Martin
authors.forename: Fionula M
authors.initials: FM
authors.lastname: Brennan
authors.forename: Ewa
authors.initials: E
authors.lastname: Paleolog
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: Brian M
authors.initials: BM
authors.lastname: Foxwell
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D051550:I-kappa B Kinase; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008222:Lymphokines / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D013583:Synovial Membrane / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016207:Cytokines; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D008222:Lymphokines; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1