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J. Biol. Chem., Vol. 277, Issue 47, 45129-45140, November 22, 2002

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IKK, IKK, and NEMO/IKK Are Each Required for the NF-B-mediated Inflammatory Response Program^*

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

From the  Department of Biology, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877-0368, the ^¶ Genetics Graduate Program,  Department of Biochemistry and Cell Biology, and ^** Department of Microbiology, State University of New York, Stony Brook, New York 11794-5215, and the ^§§ Center for Applied Biomedical Research, S. Orsola University Hospital, Via Massarenti 9, Bologna 40138, Italy

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

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