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B Regulation by IB Kinase-2 in Rheumatoid Arthritis Synoviocytes1
*
Division of Rheumatology, Allergy and Immunology, University of California San Diego School of Medicine, La Jolla, CA; and
Signal Research Division of Celgene, San Diego, CA
I
B kinase-1 and IB kinase-2 (IKK1 and IKK2; also called
IKK
and IKK
, respectively) are part of the signal complex that
regulates NF-B activity in many cell types, including
fibroblast-like synoviocytes (FLS). We determined which of these two
kinases is responsible for cytokine-induced NF-B activation in
synoviocytes and assessed the functional consequences of IKK1 or IKK2
overexpression and inhibition. FLS were infected with adenovirus
constructs encoding either wild-type (wt) IKK1 or IKK2, the dominant
negative (dn) mutant of both kinases, or a control construct encoding
green fluorescence protein. Analysis of the NF-B pathway revealed
that cytokine-induced IKK activation, IB degradation, and NF-B
activation was prevented in cells expressing the IKK2 dn mutant,
whereas baseline NF-B activity was increased by IKK2 wt. In
addition, synthesis of IL-6 and IL-8, as well as expression of ICAM-1
and collagenase, was only increased by IKK2 wt, and their
cytokine-induced production was abrogated by IKK2 dn mutant. However,
the IKK1 dn mutant did not inhibit cytokine-mediated activation of
NF-B or any of the functional assays. These data indicate that IKK2
is the key convergence pathway for cytokine-induced NF-B activation.
Furthermore, IKK2 regulates adhesion molecule, matrix
metalloproteinase, and cytokine production in
FLS.
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