Phosphatidylinositol 3-Kinase in Interleukin 1 Signaling

Abstract

The signaling mechanisms utilized by the proinflammatory cytokine interleukin-1 (IL-1) to activate the transcription factors NFB 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 3-kinase-specific inhibitors, wortmannin and a dominant-negative mutant of the p85 subunit, inhibited IL-1-induced activation of both NFB and AP-1. Transient transfection experiments indicated that whereas overexpression of PI 3-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-1-inducible signals to fully activate NFB-dependent gene expression. In this regard, cotransfection studies suggested that PI 3-kinase may functionally interact with the recently-identified IL-1-receptor-associated kinase to activate NFB. 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 NFB and AP-1.The biological processes of growth, differentiation, and immunity are dependent on the highly regulated action of transcription factor families such as NFB and activator protein-1 (AP-1).

Inhibitors of NF-κB signaling: 785 and counting

“…However, none of these molecules inhibits IkBa degradation, NF-kB nuclear translocation or DNA binding (Bergmann et al, 1998). In another study, LY294,002 and wortmannin (both PI-3 kinase inhibitors) have been used to block IL-1-induced NF-kB activation of a reporter gene (Reddy et al, 1997;Sizemore et al, 1999). LY294,002 did not inhibit IkBa degradation or NF-kB DNA binding, but it did block IL-1-stimulated phosphorylation of NF-kB, especially the RelA subunit.…”

Diverse agents act at multiple levels to inhibit the Rel/NF-κB signal transduction pathway

“…However, none of these molecules inhibits IkBa degradation, NF-kB nuclear translocation or DNA binding (Bergmann et al, 1998). In another study, LY294,002 and wortmannin (both PI-3 kinase inhibitors) have been used to block IL-1-induced NF-kB activation of a reporter gene (Reddy et al, 1997;Sizemore et al, 1999). LY294,002 could not inhibit IkBa degradation or NF-kB DNA binding, but it could block IL-1-stimulated phosphorylation of NF-kB, especially the p65/RelA subunit.…”

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

“…There is overwhelming evidence that lipid second messengers play a crucial role in many biological processes that define and control the fate of cells (for a review, see Reddy et al, 1997). Lipid second messengers are generated by phosphoinositide 3 H -kinases (PI3-K), a group of enzymes that mediate phosphorylation at the 3 H position of the inositol ring of phosphatidylinositol.…”