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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Phosphoinositide 3-Kinase γ Inhibition Plays a Crucial Role in Early Steps of Inflammation by Blocking Neutrophil Recruitment

Chiara Ferrandi, Vittoria Ardissone, Pamela Ferro, Thomas Rückle, Paola Zaratin, Elena Ammannati, Ehud Hauben, Christian Rommel and Rocco Cirillo
Journal of Pharmacology and Experimental Therapeutics September 2007, 322 (3) 923-930; DOI: https://doi.org/10.1124/jpet.107.123026
Chiara Ferrandi
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Vittoria Ardissone
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Pamela Ferro
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Thomas Rückle
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Paola Zaratin
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Elena Ammannati
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Ehud Hauben
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Christian Rommel
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Rocco Cirillo
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Abstract

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.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.123026.

  • ABBREVIATIONS: PI3K, phosphoinositide 3-kinase; IL, interleukin; MIP, macrophage inflammatory protein; RANTES, regulated on activation normal T cell expressed and secreted; r-hRANTES, recombinant human regulated on activation normal T cell expressed and secreted; LY294002, morpholin-4-yl-8-phenyl-chromen-4-one; AS041164, 5-benzo[1,3]dioxol-5-ylmethylene-thiazolidine-2,4-dione; PIR, phagocytic response; PBS, phosphate-buffered saline; FACS, flow analyzer cell sorter; PEC, peritoneal exudate cell; PMN, polymorphonuclear neutrophil; AKT, protein kinase B.

  • Received March 20, 2007.
  • Accepted May 24, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 387 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 387, Issue 1
1 Oct 2023
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Phosphoinositide 3-Kinase γ Inhibition Plays a Crucial Role in Early Steps of Inflammation by Blocking Neutrophil Recruitment

Chiara Ferrandi, Vittoria Ardissone, Pamela Ferro, Thomas Rückle, Paola Zaratin, Elena Ammannati, Ehud Hauben, Christian Rommel and Rocco Cirillo
Journal of Pharmacology and Experimental Therapeutics September 1, 2007, 322 (3) 923-930; DOI: https://doi.org/10.1124/jpet.107.123026

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Phosphoinositide 3-Kinase γ Inhibition Plays a Crucial Role in Early Steps of Inflammation by Blocking Neutrophil Recruitment

Chiara Ferrandi, Vittoria Ardissone, Pamela Ferro, Thomas Rückle, Paola Zaratin, Elena Ammannati, Ehud Hauben, Christian Rommel and Rocco Cirillo
Journal of Pharmacology and Experimental Therapeutics September 1, 2007, 322 (3) 923-930; DOI: https://doi.org/10.1124/jpet.107.123026
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