Phosphatidylinositol 3-kinase mediates interleukin-l-induced activation of NFB and AP-1 Shrikanth

The signaling mechanisms utilized by the proinfiammatorv cytokine interleukin-1 (IL-1) to activate lhe transcription factors NF,II and AP-I are poorly detined. Identification of proteins Iha interact with the II,-I recep tors may help elucidate these mechanisms. \Vo present evidence here thal 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 1 receptor with the p85 subunit ofPI 3-kinase. Furthermore, two PI 3kinasespecific inhibitors, wortmannin and a (lominanl negative mutant of the regulalory t85 subunit of PI 3-kinase. inhibited IL 1 induced activation of NI.'B and AP-I indicating that PI :/ kinase is nece,sarv for their activation. Transient transfection experiments indicated that while PI 3-kinase overexpression may be sufficient to induce AP 1 and increase nuclear c-fos protein levels. PI 3kinase may need to cooperate wit h ot her IL I:ind ucible signals to fully activate NF,B dependent gene expression. In this regard 'otransh, ction studies sug: gested that PI 3-kinase may functionally interat with the recently identified IL I receptor-associated kinase (IRAK) to activate NFML Our results thus indicate that PI 3-kinase is a nvel signal transducer in IL 1 signaling and that il mav differentially mediate the activation of NF,'B and A[' 1.