title: PI3K inhibitors LY294002 and IC87114 reduce inflammation in carrageenan-induced paw oedema and down-regulate inflammatory gene expression in activated macrophages.
abstract: PI3K/Akt pathway is a well-characterized pathway controlling cellular processes such as proliferation, migration and survival, and its role in cancer is vastly studied. There is also evidence to suggest the involvement of this pathway in the regulation of inflammatory responses. In this study, an attempt was made to investigate the role of PI3Ks in acute inflammation in vivo using pharmacological inhibitors against PI3Ks in the carrageenan-induced paw oedema model. A non-selective PI3K inhibitor LY294002 and a PI3Kδ-selective inhibitor IC87114 were used. Both of these inhibitors reduced inflammatory oedema upon carrageenan challenge in the mouse paw. To explain this result, the effects of the two inhibitors on inflammatory gene expression were investigated in activated macrophages. LY294002 and IC87114 prevented Akt phosphorylation as expected and down-regulated the expression of inflammatory factors IL-6, MCP-1,TNFα and iNOS. These findings suggest that PI3K inhibitors could be used to attenuate inflammatory responses and that the mechanism of action behind this effect is the down-regulation of inflammatory gene expression.
authors: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
authors: Heikki
authors: H
authors: Eräsalo
authors: Mirka
authors: M
authors: Laavola
authors: Mari
authors: M
authors: Hämäläinen
authors: Tiina
authors: T
authors: Leppänen
authors: Riina
authors: R
authors: Nieminen
authors: Eeva
authors: E
authors: Moilanen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002351:Carrageenan / Q000009:adverse effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology*; D015536:Down-Regulation; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000225:Adenine; D002351:Carrageenan; D018932:Chemokine CCL2; D002867:Chromones; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D009025:Morpholines; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; C491768:Ccl2 protein, mouse; C477872:IC 87114; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496317:Nos2 protein, mouse