IKKα, IKKβ, and NEMO/IKKγ are each required for the NF-κB-mediated inflammatory response program

Xiang Li, Paul E. Massa, Adedayo Hanidu, Gregory W. Peet, Patrick Aro, Ann Savitt, Sheenah Mische, Jun Li, Kenneth B. Marcu

Research output: Contribution to journalArticlepeer-review

Abstract

The IKKβ and NEMO/IKKγ subunits of the NF-κB-activating signalsome complex are known to be essential for activating NF-κB by inflammatory and other stress-like stimuli. However, the IKKα subunit is believed to be dispensable for the latter responses and instead functions as an in vivo mediator of other novel NF-κB-dependent and -independent functions. In contrast to this generally accepted view of IKKα's physiological functions, we demonstrate in mouse embryonic fibroblasts (MEFs) that, akin to IKKβ and NEMO/IKKγ, IKKα is also a global regulator of tumor necrosis factor α- and IL-1-responsive IKK signalsome-dependent target genes including many known NF-κB targets such as serum amyloid A3, C3, interleukin (IL)-6, IL-11, IL-1 receptor antagonist, vascular endothelial growth factor, Ptx3, β2-microglobulin, IL-1α, 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-κB-dependent target genes were preferentially dependent on IKKα or IKKβ. Constitutive expression of a trans-dominant IκBα superrepressor (IκBαSR) in wild type MEFs confirmed that these signalsome-dependent target genes were also dependent on NF-κB. A subset of NF-κB 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-κB in established MEFs. Overall, a sizable number of novel NF-κB/IKK-dependent genes were identified including Secreted Frizzled, cadherin 13, protocadherin 7, CCAAT/enhancer-binding protein-β and -δ, osteoprotegerin, FOXC2 and FOXF2, BMP-2, p75 neurotrophin receptor, caspase-11, guanylate-binding proteins 1 and 2, ApoJ/clusterin, interferon (α and β) 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-κB/IKK-induced gene, suggesting that IKK-mediated NF-κB activation can coordinately illicit negative effects on STAT signaling.

Original languageEnglish
Pages (from-to)45129-45140
Number of pages12
JournalJournal of Biological Chemistry
Volume277
Issue number47
DOIs
Publication statusPublished - Nov 22 2002

ASJC Scopus subject areas

  • Biochemistry

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