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PMID: 12221085 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program.

The Journal of biological chemistry ·Vol. 277 ·No. 47 ·2002-11-22 ·Pages 45129-40

Li X, Massa PE, Hanidu A, Peet GW, Aro P, Savitt A, Mische S, Li J, Marcu KB

Abstract

The IKKbeta and NEMO/IKKgamma subunits of the NF-kappaB-activating signalsome complex are known to be essential for activating NF-kappaB by inflammatory and other stress-like stimuli. However, the IKKalpha subunit is believed to be dispensable for the latter responses and instead functions as an in vivo mediator of other novel NF-kappaB-dependent and -independent functions. In contrast to this generally accepted view of IKKalpha's physiological functions, we demonstrate in mouse embryonic fibroblasts (MEFs) that, akin to IKKbeta and NEMO/IKKgamma, IKKalpha is also a global regulator of tumor necrosis factor alpha- and IL-1-responsive IKK signalsome-dependent target genes including many known NF-kappaB targets such as serum amyloid A3, C3, interleukin (IL)-6, IL-11, IL-1 receptor antagonist, vascular endothelial growth factor, Ptx3, beta(2)-microglobulin, IL-1alpha, Mcp-1 and -3, RANTES (regulated on activation normal T cell expressed and secreted), Fas antigen, Jun-B, c-Fos, macrophage colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor. Only a small number of NF-kappaB-dependent target genes were preferentially dependent on IKKalpha or IKKbeta. Constitutive expression of a trans-dominant IkappaBalpha superrepressor (IkappaBalphaSR) in wild type MEFs confirmed that these signalsome-dependent target genes were also dependent on NF-kappaB. A subset of NF-kappaB target genes were IKK-dependent in the absence of exogenous stimuli, suggesting that the signalsome was also required to regulate basal levels of activated NF-kappaB in established MEFs. Overall, a sizable number of novel NF-kappaB/IKK-dependent genes were identified including Secreted Frizzled, cadherin 13, protocadherin 7, CCAAT/enhancer-binding protein-beta and -delta, osteoprotegerin, FOXC2 and FOXF2, BMP-2, p75 neurotrophin receptor, caspase-11, guanylate-binding proteins 1 and 2, ApoJ/clusterin, interferon (alpha and beta) receptor 2, decorin, osteoglycin, epiregulin, proliferins 2 and 3, stromal cell-derived factor, and cathepsins B, F, and Z. SOCS-3, a negative effector of STAT3 signaling, was found to be an NF-kappaB/IKK-induced gene, suggesting that IKK-mediated NF-kappaB activation can coordinately illicit negative effects on STAT signaling.

MeSH Terms
Animals Cells, Cultured Embryo, Mammalian/anatomy & histology Fibroblasts/cytology,drug effects,physiology Gene Expression Regulation/immunology,physiology Humans I-kappa B Kinase I-kappa B Proteins/genetics,metabolism Inflammation/genetics,metabolism Interleukin-1/pharmacology Macromolecular Substances Mice Molecular Sequence Data NF-KappaB Inhibitor alpha NF-kappa B/antagonists & inhibitors,metabolism Oligonucleotide Array Sequence Analysis Protein Serine-Threonine Kinases/genetics,metabolism Protein Subunits Signal Transduction/physiology Tumor Necrosis Factor-alpha/pharmacology
Chemicals
I-kappa B Proteins Interleukin-1 Macromolecular Substances NF-kappa B NFKBIA protein, human Nfkbia protein, mouse Protein Subunits Tumor Necrosis Factor-alpha NF-KappaB Inhibitor alpha Protein Serine-Threonine Kinases CHUK protein, human Chuk protein, mouse I-kappa B Kinase IKBKB protein, human IKBKE protein, human Ikbkb protein, mouse Ikbke protein, mouse
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Li Xiang
Department of Biology, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877-0368, USA.
Massa Paul E
Hanidu Adedayo
Peet Gregory W
Aro Patrick
Savitt Ann
Mische Sheenah
Li Jun
Marcu Kenneth B
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M205165200
Published
2002-11-22
Epub
2002-00-06
Pages
45129-40
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC1201411
Subset
IM
Grants
NIAID NIH HHS · R01 AI057555 · United States
NIGMS NIH HHS · GM26939 · United States
External Links
PubMed source DOI: 10.1074/jbc.M205165200 PMC Full Text View journal details
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