RT Journal Article
SR Electronic
T1 Phosphoinositide 3-Kinase γ Inhibition Plays a Crucial Role in Early Steps of Inflammation by Blocking Neutrophil Recruitment
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 923
OP 930
DO 10.1124/jpet.107.123026
VO 322
IS 3
A1 Chiara Ferrandi
A1 Vittoria Ardissone
A1 Pamela Ferro
A1 Thomas Rückle
A1 Paola Zaratin
A1 Elena Ammannati
A1 Ehud Hauben
A1 Christian Rommel
A1 Rocco Cirillo
YR 2007
UL http://jpet.aspetjournals.org/content/322/3/923.abstract
AB 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 PI3Kγ 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 PI3Kγ-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 PI3Kγ pathway plays an important role in controlling neutrophil chemotaxis during early steps of inflammation.