Phosphoinositide 3-kinases (PI3Ks) are known to be involved in a variety of cellular responses such as cell survival, proliferation, differentiation and cell migration. Recently, PI3Ks have been associated with the pathogenesis of asthma because various immune cells regulate allergic responses. Among the three classes of PI3Ks, the roles of PI3Kγ and PI3Kδ in allergic responses have attracted particular attention. In a previous report, allergic airway hyperresponsiveness (AHR), inflammation and airway remodeling in an ovalbumin-induced asthma model were decreased in PI3Kγ-deficient mice compared with wild-type mice. In addition, AHR and inflammation were attenuated by administration of a selective PI3Kδ inhibitor in a murine model of asthma. These results indicate that PI3Kγ and PI3Kδ may be new therapeutic targets for asthma. However, PI3Kγ and PI3Kδ may differ in terms of the mechanism of regulation. In this review, we focus on the roles of PI3Kγ and PI3Kδ in the pathogenesis of asthma and discuss the mechanistic differences between PI3Kγ and PI3Kδ.

Keywords:
Airway inflammation, Allergy, Asthma, Phosphoinositide 3-kinase, PI3K inhibitors
1.
Toker A, Cantley LC: Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 1997;387:673–676.
2.
Wymann MP, Björklöf K, Calvez R, Finan P, Thomast M, Trifilieff A, Barbier M, Altruda F, Hirsch E, Laffargue M: Phosphoinositide 3-kinase gamma: a key modulator in inflammation and allergy. Biochem Soc Trans 2003;31:275–280.
3.
Chihara J: Molecular mechanisms of eosinophil activation in allergic diseases. Clin Exp All Rev 2005;5:46–49.
4.
Larché M, Robinson DS, Kay AB: The role of T lymphocytes in the pathogenesis of asthma. J Allergy Clin Immunol 2003;111:450–463.
5.
Duan W, Aguinaldo Datiles AM, Leung BP, Vlahos CJ, Wong WS: An anti-inflammatory role for a phosphoinositide 3-kinase inhibitor LY294002 in a mouse asthma model. Int Immunopharmacol 2005;5:495–502.
6.
Kwak YG, Song CH, Yi HK, Hwang PH, Kim JS, Lee KS, Lee YC: Involvement of PTEN in airway hyperresponsiveness and inflammation in bronchial asthma. J Clin Invest 2003;111:1083–1092.
7.
Bi L, Okabe I, Bernard DJ, Wynshaw-Boris A, Nussbaum RL: Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem 1999;274:10963–10968.
8.
Bi L, Okabe I, Bernard DJ, Nussbaum RL: Early embryonic lethality in mice deficient in the p110beta catalytic subunit of PI 3-kinase. Mamm Genome 2002;13:169–172.
9.
Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD: Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. FASEB J 2006;20:455–465.
10.
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 p110delta in generation of type 2 cytokine responses and allergic airway inflammation. Eur J Immunol 2007;37:416–424.
11.
Takeda M, Ito W, Tanabe M, Ueki S, Kato H, Kihara J, Tanigai T, Chiba T, Yamaguchi K, Kayaba H, Imai Y, Okuyama K, Ohno I, Sasaki T, Chihara J: Allergic airway hyperresponsiveness, inflammation, and remodeling do not develop in phosphoinositide 3-kinase gamma-deficient mice. J Allergy Clin Immunol 2009;123:805–812.
12.
Davies DE, Wicks J, Powell RM, Puddicombe SM, Holgate ST: Airway remodeling in asthma: new insights. J Allergy Clin Immunol 2003;111:215–225.
13.
Ito W, Kanehiro A, Matsumoto K, Hirano A, Ono K, Maruyama H, Kataoka M, Nakamura T, Gelfand EW, Tanimoto M: Hepatocyte growth factor attenuates airway hyperresponsiveness, inflammation, and remodeling. Am J Respir Cell Mol Biol2005;32:268–280.
14.
Georas SN, Guo J, De Fanis U, Casolaro V: T-helper cell type-2 regulation in allergic disease. Eur Respir J 2005;26:1119–1137.
15.
Platts-Mills TA: The role of immunoglobulin E in allergy and asthma. Am J Respir Crit Care Med 2001;164:1–5.
16.
Lim DH, Cho JY, Song DJ, Lee SY, Miller M, Broide DH: PI3K gamma-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling. Am J Physiol Lung Cell Mol Physiol 2009;296:L210–L219.
17.
Pinho V, Souza DG, Barsante MM, Hamer FP, De Freitas MS, Rossi AG, Teixeira MM: Phosphoinositide-3 kinases critically regulate the recruitment and survival of eosinophils in vivo: importance for the resolution of allergic inflammation. J Leukoc Biol 2005;77:800–810.
18.
Fruman DA, Snapper SB, Yballe CM, Davidson L, Yu JY, Alt FW, Cantley LC: Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Science 1999;283:393–397.
19.
Suzuki H, Terauchi Y, Fujiwara M, Aizawa S, Yazaki Y, Kadowaki T, Koyasu S: Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase. Science 1999;283:390–392.
20.
Salogni L, Musso T, Bosisio D, Mirolo M, Jala VR, Haribabu B, Locati M, Sozzani S: Activin A induces dendritic cell migration through the polarized release of CXC chemokine ligands 12 and 14. Blood 2009;113:5848–5856.
21.
Del Prete A, Vermi W, Dander E, Otero K, Barberis L, Luini W, Bernasconi S, Sironi M, Santoro A, Garlanda C, Facchetti F, Wymann MP, Vecchi A, Hirsch E, Mantovani A, Sozzani S: Defective dendritic cell migration and activation of adaptive immunity in PI3Kgamma-deficient mice. EMBO J 2004;23:3505–3515.
22.
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 p110delta phosphoinositide 3-kinase in the allergic response. Nature 2004;431:1007–1011.
23.
Ali K, Camps M, Pearce WP, Ji H, Rückle T, Kuehn N, Pasquali C, Chabert C, Rommel C, Vanhaesebroeck B: Isoform-specific functions of phosphoinositide 3-kinases: p110 delta but not p110 gamma promotes optimal allergic responses in vivo. J Immunol 2008;180:2538–2544.
24.
Endo D, Gon Y, Nunomura S, Yamashita K, Hashimoto S, Ra C: PI3Kγ differentially regulates FcεRI-mediated degranulation and migration of mast cells by and toward antigen. Int Arch Allergy Immunol 2009;149:66–72.
25.
Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I, Joza N, Mak TW, Ohashi PS, Suzuki A, Penninger JM: Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 2000;287:1040–1046.
26.
Randis TM, Puri KD, Zhou H, Diacovo TG: Role of PI3Kdelta and PI3Kgamma in inflammatory arthritis and tissue localization of neutrophils. Eur J Immunol 2008;38:1215–1224.
27.
Doukas J, Eide L, Stebbins K, Racanelli-Layton A, Dellamary L, Martin M, Dneprovskaia E, Noronha G, Soll R, Wrasidlo W, Acevedo LM, Cheresh DA: Aerosolized phosphoinositide 3-kinase gamma/delta inhibitor TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease. J Pharmacol Exp Ther 2009;328:758–765.
28.
Lai WQ, Goh HH, Bao Z, Wong WS, Melendez AJ, Leung BP: The role of sphingosine kinase in a murine model of allergic asthma. J Immunol 2008;180:4323–4329.
29.
Thomas M, Edwards MJ, Sawicka E, Duggan N, Hirsch E, Wymann MP, Owen C, Trifilieff A, Walker C, Westwick J, Finan P: Essential role of phosphoinositide 3-kinase gamma in eosinophil chemotaxis within acute pulmonary inflammation. Immunology 2009;126:413–422.
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2010
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