Phosphoinositide 3-kinase gamma inhibition plays a crucial role in early steps of inflammation by blocking neutrophil recruitment.
Leukocyte trafficking to inflammatory sites is a gradual process, which is dominated in its early phases by chemokine- and cytokine-mediated neutrophil recruitment. The chemokine regulated on activation normal T cell expressed and secreted (RANTES) has been shown to be highly expressed in the joints of patient with rheumatoid arthritis and to promote leukocyte trafficking into the synovial tissue. In this study, we investigated the effect of RANTES in a murine model of peritoneal chemotaxis, and we found that RANTES dose-dependently induces neutrophil recruitment. Then, through morphological and histological analyses, we observed that activated neutrophils represent the major infiltrating population in response to RANTES chemotactic stimulus. Furthermore, we demonstrated that oral administration of either nonisoform-specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (morpholin-4-yl-8-phenylchromen-4-one) or selective PI3Kgamma inhibitor AS041164 (5-benzo[1,3]dioxol-5-ylmethylene-thiazolidine-2,4-dione) blocks RANTES-induced chemotaxis and reduces the level of AKT phosphorylation. Because the two compounds showed a similar pharmacokinetic profile in terms of bioavailability and half-life after oral route administration, the selective inhibition of the PI3Kgamma-isoform pathway through AS041164 was three times more potent in reducing neutrophil recruitment. Finally, to confirm the blockade of neutrophil infiltration that occurs in the early phase of the inflammatory response, AS041164 was also tested in a model of carrageenan-induced paw edema in rats. Therefore, the PI3Kgamma pathway plays an important role in controlling neutrophil chemotaxis during early steps of inflammation.
Ferrandi
Chiara
C
Molecular Medicine, Pharmacology Department, RBM/Merck Serono Via Ribes 1, Colleretto Giacosa (TO), Italy. chiara.ferrandi@merckserono.net
Ardissone
Vittoria
V
Ferro
Pamela
P
Rückle
Thomas
T
Zaratin
Paola
P
Ammannati
Elena
E
Hauben
Ehud
E
Rommel
Christian
C
Cirillo
Rocco
R
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018946:Chemokine CCL5 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D010537:Peritoneum; D000081082:Phosphoinositide-3 Kinase Inhibitors
D018946:Chemokine CCL5; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse