MECHANISMS OF SIGNAL TRANSDUCTION
Inhibition of Interleukin-1β-induced NF-κB Activation by Calcium/Calmodulin-dependent Protein Kinase Kinase Occurs through Akt Activation Associated with Interleukin-1 Receptor-associated Kinase Phosphorylation and Uncoupling of MyD88*

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Calcium/calmodulin-dependent protein kinase kinase (CaMKK) and Akt are two multifunctional kinases involved in many cellular responses. Although Akt and Ca2+ signals have been implicated in NF-κB activation in response to certain stimuli, these results are still controversial, and the mechanism(s) involved remains unknown. In this study, we show the roles that CaMKK and Akt play in regulating interleukin-1β (IL-1β)-induced NF-κB signaling. In human embryonic kidney 293 cells, IL-1β induces IκB kinase β (IKKβ) activation, IκBα degradation, NF-κB transactivation, and weak Akt activation. A CaMKK inhibitor (KN-93) and phosphatidylinositol 3-kinase inhibitors (wortmannin and LY294002) do not inhibit IL-1β-induced NF-κB activation. However, IL-1β-induced NF-κB activity is attenuated by increased intracellular calcium in response to ionomycin, UTP, or thapsigargin or by overexpression of CaMKKc and/or Akt. Ionomycin and CaMKKc overexpression increases Akt phosphorylation on Thr308 and enzyme activity. Under these conditions or upon overexpression of wild type Akt, IL-1β-induced IKKβ activity is diminished. Furthermore, a dominant negative mutant of Akt abolishes IKKβ inhibition by CaMKKc and ionomycin, suggesting that Akt acts as a mediator of CaMKK signaling to inhibit IL-1β-induced IKK activity at an upstream target site. We have also identified a novel interaction between CaMKK-stimulated Akt and interleukin-1 receptor-associated kinase 1 (IRAK1), which plays a key role in IL-1β-induced NF-κB activation. CaMKKc and Akt overexpression decreases IRAK1-mediated NF-κB activity and its association with MyD88 in response to IL-1β stimulation. Furthermore, CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-κB activation. Taken together, these results indicate a novel regulatory mechanism for IL-1β signaling and suggest that CaMKK-dependent Akt activation inhibits IL-1β-induced NF-κB activation through interference with the coupling of IRAK1 to MyD88.

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Published, JBC Papers in Press, April 25, 2002, DOI 10.1074/jbc.M106014200

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This work was supported by National Science Council of Taiwan Grant NSC 90-2320-B002-085.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.