CD40 engagement enhances eosinophil survival through induction of cellular inhibitor of apoptosis protein 2 expression: Possible involvement in allergic inflammation.
[en] BACKGROUND: CD40 engagement enhances eosinophil survival, suggesting a role for this receptor in the development of eosinophilia. OBJECTIVE: We examined whether CD40 enhances eosinophil survival by inducing the expression of antiapoptotic proteins. Three members of the inhibitor of apoptosis protein (IAP) family, namely cellular (c)-IAP1, c-IAP2, and XIAP, and 2 antiapoptotic proteins of the Bcl-2 family, namely Bcl-x(L) and Bfl-1/A1, were investigated. METHODS: Blood and sputum were obtained from healthy subjects and atopic asthmatic patients. Blood eosinophils were isolated by means of magnetic selection. Expression of CD40, IAPs, and Bcl-2 proteins was investigated by using flow cytometry, immunoblotting, or both. CD40 stimulation was achieved with agonistic antibodies or soluble ligands. Apoptosis was assessed by staining with propidium iodide and FITC-conjugated annexin-V. c-IAP2 expression was inhibited with antisense oligonucleotides. RESULTS: Freshly isolated eosinophils from healthy and asthmatic patients did not express CD40. Conversely, eosinophils expressed CD40 spontaneously when cultured for 48 hours. At this time point, CD40 stimulation significantly delayed eosinophil apoptosis. Inhibition of eosinophil apoptosis was accompanied by induction of c-IAP2 but not c-IAP1, XIAP, Bcl-x(L), or Bfl-1/A1 expression. Antisense knockdown of c-iap2 abolished CD40-induced enhancement of eosinophil survival. Sputum cells from asthmatic patients, unlike those from healthy subjects, substantially expressed CD40 and c-IAP2. Moreover, a strong correlation was found between the percentage of eosinophils in the sputum from asthmatic patients and the sputum level of CD40 and c-IAP2 expression. CONCLUSION: The results demonstrate that CD40 engagement enhances eosinophil survival through induction of c-IAP2 expression and suggest a role for this mechanism in allergic inflammation.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Bureau, Fabrice ; Université de Liège - ULiège > Département de sciences fonctionnelles > GIGA-R : Biochimie et biologie moléculaire
Pastoret, Paul-Pierre ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires > Département des maladies infectieuses et parasitaires
Louis, Renaud ; Université de Liège - ULiège > Département des sciences cliniques > Pneumologie - Allergologie
Lekeux, Pierre ; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie - Doyen de la Faculté de Médecine vétérinaire
Language :
English
Title :
CD40 engagement enhances eosinophil survival through induction of cellular inhibitor of apoptosis protein 2 expression: Possible involvement in allergic inflammation.
Simon HU, Blaser K. Inhibition of programmed eosinophil death: a key pathogenic event for eosinophilia? Immunol Today 1996;16:53-5.
Owen WF Jr, Rothenberg ME, Silberstain DS, Gasson JC, Stevens RL, Austen KF, et al. Regulation of human eosinophd viability, density, and function by granulocyte/macrophage colony-stimulating factor in the presence of 3T3 fibroblasts. J Exp Med 1987;166:129-41.
Rothenberg ME, Owen WF Jr, Silberstein DS, Woods J, Sobermen RJ, Austen KF, et al. Human eosinophils have prolonged survival, enhanced functional properties, and become hypodense when exposed to human interleukin 3. J Clin Invest 1988;81:1986-92.
Rothenberg ME, Petersen J, Stevens RL, Silberstein DS, McKenzie DT, Austen KF, et al. II-5-dependent conversion of normodense human eosinophils to the hypodense phenotype uses 3T3 fibroblasts for enhanced viability, accelerated hypodensity, and sustained antibody-dependent cytotoxicity. J Immunol 1989;143:2311-6.
Kay AB, Ying S, Varney V, Gaga, Durham SR, Moqbel R, et al. Messenger RNA espression of the cytokine gene cluster, interleukin 3 (IL-3), IL-4, IL-5, and granulocyte/macrophage colony-stimulating factor, in allergen-induced late-phase cutaneous reactions in atopic subjects. J Exp Med 1991;173:775-8.
Simon HU, Yousefi S, Schranz C, Schpowal A, Bachert C, Blaser K. Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia. J Immunol 1997;158:3902-8.
Walker C, Virchow JC, Bruijnzeel PL, Blaser K. T cell subsets and their soluble products regulate eosinophilia in allergic and nonallergic asthma. J Immunol 1991;146:1829-35.
Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 1998;16:111-35.
Afford SC, Randbawa S, Eliopoulos AG, Hubscher SG, Young LS, Adams DH. CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med 1999;189:441-6.
Eliopoulos AG, Davies C, Knox PG, Gallagher NJ, Afford SC, Adams DH, et al. CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily. Mol Cell Biol 2000;20:5503-15.
Gordon J. CD40 and its ligand: central players in B lymphocyte survival, growth, and differentiation. Blood Rev 1995;9:53-6.
Merino R, Grillot DA, Simonian PL, Muthukkumar S, Fanslow WC, Bondada S, et al. Modulation of anti-IgM-induced B cell apoptosis by Bcl-xL and CD40 in WEHI-231 cells. Dissociation from cell cycle arrest and dependence on the avidity of the antibody-IgM receptor interaction. J Immunol 1995;155:3830-8.
Lee HH, Dadgostar H, Cheng Q, Shu J, Cheng G. NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proc Natl Acad Sci U S A 1999;96:9136-41.
Kuss AW, Knodel M, Berberich-Siebelt F, Lindemann D, Schimpl A, Berberich I. Al expression is stimulated by CD40 in B cells and rescues WEHI 231 cells from anti-IgM-induced cell death. Eur J Immunol 1999;29:3077-88.
Craxton A, Shu G, Graves JD, Saklatvala J, Krebs EG, Clark EA. P38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes. J Immunol 1998;161:3225-36.
Ohkawara Y, Lim KG, Xing Z, Glibetic M, Nakano K, Dolovich J, et al. CD40 expression by human peripheral blood eosinophils. J Clin Invest 1996;97:1761-6.
Cataldo D, Munaut C, Noël A, Bartsch P, Foidart JM, Louis R. MMP-2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol 2000;123:259-67.
Bureau F, Vanderplasschen A, Jaspar F, Minner F, Pastoret PP, Merville MP, et al. Constitutive nuclear factor-?B activity preserves homeostasis of quiescent mature lymphocytes and granulocytes by controlling the expression of distinct Bcl-2 family proteins. Blood 2002;99:3683-91.
Van Kooten C, Banchereau J. Functions of CD40 on B cells, dendritic cells and other cells: Curr Opin Immunol 1997;9:330-7.
Alderson MR, Armitage RJ, Tough TW, Strockbine L, Fanslow WC, priggs MK. CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40. J Exp Med 1993;178:669-74.
Gauchat JF, Henchoz S, Fattah D, Mazzei G, Aubry JP, Jomotte T, et al. CD40 ligand is functionally expressed on human eosinophils. Eur J Immunol 1995;25:863-5.
Ishihara C, Ochiai K, Kagami M, Takashahi H, Matsuyama G, Yoshida S, et al. Human peripheral eosinophils express functional interferon-gamma receptors (IFN-gammaR). Clin Exp Immunol 1997;110:524-9.
DiPersio J, Billing P, Kaufman S, Eghtesady P, Williams RE, Gasson JC. Characterization of the human granulocyte-macrophage colony-stimulating factor receptor. J Biol Chem 1988;263:1834-41.
Clem RJ, Duckett CS. The iap genes: unique arbitrors of cell death. Trends Cell Biol 1997;7:337-9.
Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 1995;83:1243-52.
Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J 1997;16:6914-25.
Hogan SP, Mould A, Kikutuni H, Ramsay AJ, Foster PS. Aeroallergen-induced eosinophilic inflammation, lung damage, and airways hyperreactivity in mice can occur independently of IL-4 and allergen-specific immunoglobulins. J Clin Invest 1997;99:1329-39.
Lei XF, Ohkawara Y, Stampfli MR, Mastruzzo C, Marr RA, Snider D, et al. Disruption of antigen-induced inflammatory responses in CD40 ligand knockout mice. J Clin Invest 1998;101:1342-53.
Mehlhop PD, van de Rijn M, Brewer JP, Kisselgof AB, Geha RS, Oettgen C, et al. CD40L, but not CD40, is required for allergen-induced bronchial hyperresponsiveness in mice. Am J Respir Cell Mol Biol 2000;23:646-51.
Ward I, Dransfield I, Chilvers ER, Haslett I, Rossi AG. Pharmacological manipulation of granulocyte apoptosis: potential therapeutic targets. Trends Pharmacol Sci 1999;20:503-9.
Jabara HH, Fu SM Geha RS Vercelli D. CD40 and IgE: synergism between anti-cD40 monoclonal antibody and interleukin 4 in the induction of IgE synthesis by highly purified human B cells. J Exp Med 1990;172:1861-4.
