Phosphatidylinositol 3-kinase in interleukin 1 signaling - Physical interaction with the interleukin 1 receptor and requirement in NF kappa B and AP-1 activation

The signaling mechanisms utilized by the proinflammatory cytokine interleukin-l (IL-1) to activate the transcription factors NF kappa B and activator protein-1 (AP-1) are poorly defined. We present evidence here that IL-1 not only stimulates a dramatic increase in phosphatidylinositol 3-kinase (PI 3-kinase) activity but also induces the physical interaction of its type I receptor with the p85 regulatory subunit of PI 3-kinase. Furthermore, two PI S-kinase-specific inhibitors, wortmannin and a dominant-negative mutant of the p85 subunit, inhibited IL-induced activation of both NF kappa B and AP-1. Transient transfection experiments indicated that whereas overexpression of PI S-kinase may be sufficient to induce AP-1 and increase nuclear c-Fos protein levels, PI 3-kinase may need to cooperate with other IL-l-inducible signals to fully activate NF kappa B-dependent gene expression. In this regard, cotransfection studies suggested that PI 3-kinase may functionally interact with the recently-identified IL-l-receptor-associated kinase to activate NF kappa B. Our results thus indicate that PI 3-kinase is a novel signal transducer in IL-1 signaling and that it may differentially mediate the activation of NF kappa B and AP-1.