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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).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.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.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.

Original publication

DOI

10.1002/art.11044

Type

Journal article

Journal

Arthritis and rheumatism

Publication Date

07/2003

Volume

48

Pages

1901 - 1912

Addresses

Kennedy Institute of Rheumatology, Imperial College of Science, Technology and Medicine, London, UK.

Keywords

Synovial Membrane, Endothelium, Vascular, Umbilical Veins, Monocytes, Cells, Cultured, Fibroblasts, Macrophages, Skin, Humans, Arthritis, Rheumatoid, Collagenases, Matrix Metalloproteinases, Protein-Serine-Threonine Kinases, Lipopolysaccharides, Intercellular Signaling Peptides and Proteins, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Endothelial Growth Factors, Tumor Necrosis Factor-alpha, NF-kappa B, Interleukin-8, Interleukin-1, Interleukin-6, Cytokines, Lymphokines, I-kappa B Kinase, Matrix Metalloproteinase 2, Matrix Metalloproteinase 3, Matrix Metalloproteinase 1, Matrix Metalloproteinase 13