IL-1beta-induced phosphorylation of PKB/Akt depends on the presence of IRAK-1.
IL-1, IL-18 and LPS are recognized by specific receptor complexes of the Toll/IL-1R family, characterized by a common intracellular domain indispensable for downstream signaling. Upon ligand binding, these receptors activate the central MyD88-IRAK-TRAF6 signaling module, resulting in the activation of NF-kappaB. Ligated receptors also induce activation of other signaling cascades, suchas the PI3-kinase (PI3-K) and the p38 mitogen-activated protein kinase (MAPK) pathways. Unlike the p38MAPK pathway, which couples to the central signaling module, the PI3-K pathway seems to directly interact with the receptor molecules. Thus, activation of the PI3-K pathway is thought to be independent of the IRAK-containing signaling module. Employing two cell lines, we show that the PI3-K pathways can be activated by IL-1, IL-18 or LPS with comparable, but cell type specific kinetics, which can be correlated to biological consequences. This indicates that activation of the PI3-K pathways may be regulated by an element common for all three receptor types, the MyD88-IRAK-TRAF6 module being a candidate for this function. Using an IRAK-1-deficient cell line, we demonstrate that the IRAK-1-containing signaling module is essential for the IL-1-induced activation of the PI3-K pathway. Possible models of the interaction between IRAK-1 and the PI3-K pathway are discussed.
Neumann
Detlef
D
Hannover Medical School, Department of Pharmacology, Hannover, Germany.
Lienenklaus
Stefan
S
Rosati
Olaf
O
Martin
Michael U
MU
D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases; D020382:Interleukin-18 / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D018448:Models, Immunological; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011494:Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D053592:Interleukin-1 Receptor-Associated Kinases; D020382:Interleukin-18; D007376:Interleukin-2; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases