Phosphatidylinositol 3-kinase (PI3K) has been recognized as an important downstream effector of high-affinity receptor for IgE (FcεRI) signaling in mast cells, but little is known about the isoform specificity of PI3Ks on the FcεRI-mediated migration toward the antigen (Ag). In the present study, we explored the role of PI3Kγ on mast cell migration. The treatment of bone marrow-derived mast cells (BMMCs) with a PI3Kγ inhibitor, AS605240, significantly repressed FcεRI-induced degranulation and migration. The culture supernatants of wild-type mast cells stimulated with IgE and Ag attracted FcεRIβ–/– mast cells which did not express FcεRI on their cell surface, indicating that the migration appears to be dependent on an autocrine/paracrine secretion of soluble factors from the mast cells. Adenosine, which is produced by mast cells, showed a strong activity to attract mast cells. Pertussis toxin (PTX) significantly inhibited the migration toward both the supernatant and adenosine. The supernatant from mast cells pretreated with wortmannin (Wort) and stimulated with IgE and Ag still exhibited the activity as chemoattractant, while the BMMCs pretreated with Wort did not migrate toward the supernatant. Although PTX significantly reduced the activation of AKT/PKB and migration, PTX had no effects on degranulation. These results suggest that PI3Kγ activation through PTX-sensitive G-protein-coupled receptor as a secondary response of FcεRI cross-linking regulates FcεRI-mediated mast cell migration toward the Ag, while simultaneously activated PI3Kγ through a PTX-insensitive pathway might have an effect on degranulation.

Bradding P, Walls AF, Holgate ST: The role of the mast cell in the pathophysiology of asthma. J Allergy Clin Immunol 2006;117:1277–1284.
Marshall JS: Mast-cell responses to pathogens. Nat Rev Immunol 2004;4:787–799.
Rivera J, Gilfillan AM: Molecular regulation of mast cell activation. J Allergy Clin Immunol 2006;117:1214–1226.
Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B: Essential role for the p110δ phosphoinositide 3-kinase in the allergic response. Nature 2004;431:1007–1011.
Ali K, Camps M, Pearce WP, Ji H, Ruckle T, Kuehn N, Pasquali C, Chabert C, Rommel C, Vanhaesebroeck B: Isoform-specific functions of phosphoinositide 3-kinases: p110 δ but not p110 γ promotes optimal allergic responses in vivo. J Immunol 2008;180:2538–2544.
Gilfillan AM, Tkaczyk C: Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 2006;6:218–230.
Rommel C, Camps M, Ji H: PI3K δ and PI3K γ: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 2007;7:191–201.
Kitaura J, Kinoshita T, Matsumoto M, Chung S, Kawakami Y, Leitges M, Wu D, Lowell CA, Kawakami T: IgE- and IgE+Ag-mediated mast cell migration in an autocrine/paracrine fashion. Blood 2005;105:3222–3229.
Laffargue M, Calvez R, Finan P, Trifilieff A, Barbier M, Altruda F, Hirsch E, Wymann MP: Phosphoinositide 3-kinase γ is an essential amplifier of mast cell function. Immunity 2002;16:441–451.
Ishizuka T, Okajima F, Ishiwara M, Iizuka K, Ichimonji I, Kawata T, Tsukagoshi H, Dobashi K, Nakazawa T, Mori M: Sensitized mast cells migrate toward the antigen: a response regulated by p38 mitogen-activated protein kinase and Rho-associated coiled-coil-forming protein kinase. J Immunol 2001;167:2298–2304.
Taub D, Dastych J, Inamura N, Upton J, Kelvin D, Metcalfe D, Oppenheim J: Bone marrow-derived murine mast cells migrate, but do not degranulate, in response to chemokines. J Immunol 1995;154:2393–2402.
Sawada J, Itakura A, Tanaka A, Furusaka T, Matsuda H: Nerve growth factor functions as a chemoattractant for mast cells through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways. Blood 2000;95:2052–2058.
Hiraoka S, Furumoto Y, Koseki H, Takagaki Y, Taniguchi M, Okumura K, Ra C: Fc receptor β subunit is required for full activation of mast cells through Fc receptor engagement. Int Immunol 1999;11:199–207.
Furumoto Y, Hiraoka S, Kawamoto K, Masaki S, Kitamura T, Okumura K, Ra C: Polymorphisms in FcεRI β chain do not affect IgE-mediated mast cell activation. Biochem Biophys Res Commun 2000;273:765–771.
Bilancio A, Okkenhaug K, Camps M, Emery JL, Ruckle T, Rommel C, Vanhaesebroeck B: Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells. Blood 2006;107:642–650.
Pomel V, Klicic J, Covini D, Church DD, Shaw JP, Roulin K, Burgat-Charvillon F, Valognes D, Camps M, Chabert C, Gillieron C, Francon B, Perrin D, Leroy D, Gretener D, Nichols A, Vitte PA, Carboni S, Rommel C, Schwarz MK, Ruckle T: Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase γ. J Med Chem 2006;49:3857–3871.
McCloskey MA, Fan Y, Luther S: Chemotaxis of rat mast cells toward adenine nucleotides. J Immunol 1999;163:970–977.
Nashed BF, Zhang T, Al-Alwan M, Srinivasan G, Halayko AJ, Okkenhaug K, Vanhaesebroeck B, Hayglass KT, Marshall AJ: Role of the phosphoinositide 3-kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation. Eur J Immunol 2007;37:416–424.
Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC: Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem Sci 2005;30:194–204.
Wymann MP, Bjorklof K, Calvez R, Finan P, Thomast M, Trifilieff A, Barbier M, Altruda F, Hirsch E, Laffargue M: Phosphoinositide 3-kinase γ: a key modulator in inflammation and allergy. Biochem Soc Trans 2003;31:275–280.
Hua X, Chason KD, Fredholm BB, Deshpande DA, Penn RB, Tilley SL: Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells. J Allergy Clin Immunol 2008;122:107–113.
Nunomura S, Yoshimaru T, Ra C: Na-Tosyl-Phe chloromethyl ketone prevents granule movement and mast cell synergistic degranulation elicited by costimulation of antigen and adenosine. Life Sci 2008;83:242–249.
Tilley SL, Wagoner VA, Salvatore CA, Jacobson MA, Koller BH: Adenosine and inosine increase cutaneous vasopermeability by activating A(3) receptors on mast cells. J Clin Invest 2000;105:361–367.
Zhong H, Shlykov SG, Molina JG, Sanborn BM, Jacobson MA, Tilley SL, Blackburn MR: Activation of murine lung mast cells by the adenosine A3 receptor. J Immunol 2003;171:338–345.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.