ic-87114 and Edema

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.

Topics: Adenine; Animals; Carrageenan; Chemokine CCL2; Chromones; Down-Regulation; Edema; Enzyme Inhibitors; Inflammation; Interleukin-6; Macrophages; Mice; Morpholines; Nitric Oxide Synthase Type II; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Quinazolines; Tumor Necrosis Factor-alpha

The p110delta isoform of class I phosphoinositide 3-kinase (PI3K) plays a major role in B cell receptor signaling, while its p110gamma counterpart is thought to predominate in leukocyte chemotaxis. Consequently, emphasis has been placed on developing PI3Kgamma selective inhibitors to treat disease states that result from inappropriate tissue accumulation of leukocytes. We now demonstrate that PI3Kdelta blockade is effective in treating an autoimmune disorder in which neutrophil infiltration is required for tissue injury. Using the K/BxN serum transfer model of arthritis, in which neutrophils and leukotriene B(4) (LTB(4)) participate, we show that genetic deletion or selective inhibition of PI3Kdelta diminishes joint erosion to a level comparable to its PI3Kgamma counterpart. Moreover, the induction and progression of joint destruction was profoundly reduced in the absence of both PI3K isoforms and correlated with a limited ability of neutrophils to migrate into tissue in response to LTB(4). However, the dynamic interplay between these isoforms is not pervasive, as fMLP-induced neutrophil extravasation was primarily reliant on PI3Kgamma. Our results not only demonstrate that blockade of PI3Kdelta has potential therapeutic value in the treatment of chronic inflammatory conditions, but also provide evidence that dual inhibition of these lipid kinases may yield superior clinical results.

Topics: Adenine; Animals; Arthritis, Experimental; Chemotaxis, Leukocyte; Class I Phosphatidylinositol 3-Kinases; Class Ib Phosphatidylinositol 3-Kinase; Edema; Enzyme Inhibitors; Hindlimb; Isoenzymes; Leukotriene B4; Mice; Mice, Inbred NOD; Mice, Inbred Strains; Mice, Knockout; Mice, Transgenic; N-Formylmethionine Leucyl-Phenylalanine; Neutrophil Infiltration; Neutrophils; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Quinazolines