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J. Biol. Chem., Vol. 282, Issue 8, 5143-5151, February 23, 2007

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CD40 Ligand Binds to 51 Integrin and Triggers Cell Signaling^*

Claire Léveillé¹, Marlène Bouillon¹, Wen Guo¹, Julie Bolduc, Ehssan Sharif-Askari^¶2, Youssef El-Fakhry, Carlos Reyes-Moreno, Rejean Lapointe^**, Yahye Merhi, John A. Wilkins, and Walid Mourad^¶3

From the Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier de l'Université Laval, Québec City, Quebec G1V 4G2, the Laboratoire d'immunologie cellulaire et moléculaire, Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc, Montréal, Quebec H2X 1P1, the ^**Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Montréal, Quebec H2W 1T8, the Institut de Recherche en cardiologie, Université de Montréal, Montréal, Quebec H1T 1C8, the Manitoba Centre for Proteomics and Rheumatic Diseases Research Laboratory, Department of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 3P4, and the ^¶Département de Médecine, Université de Montréal, Montréal, Québec H3T 3J7, Canada

It was originally thought that the critical role of the CD40 ligand (CD40L) in normal and inflammatory immune responses was mainly mediated through its interaction with the classic receptor, CD40. However, data from CD40L^–/– and CD40^–/– mice suggest that the CD40L-induced inflammatory immune response involves at least one other receptor. This hypothesis is supported by the fact that CD40L stabilizes arterial thrombi through an IIb3-dependent mechanism. Here we provide evidence that soluble CD40L (sCD40L) binds to cells of the undifferentiated human monocytic U937 cell line in a CD40- and IIb3-independent manner. Binding of sCD40L to U937 cells was inhibited by anti-CD40L monoclonal antibody 5C8, anti-51 monoclonal antibody P1D6, and soluble 51. The direct binding of sCD40L to purified 51 was confirmed in a solid phase binding assay. Binding of sCD40L to 51 was modulated by the form of 51 expressed on the cell surface as the activation of 51 by Mn²⁺ or dithiothreitol resulted in the loss of sCD40L binding. Moreover, sCD40L induced the translocation of 51 to the Triton X-100-insoluble fraction of U937 cells, the rapid activation of the MAPK pathways ERK1/2, and interleukin-8 gene expression. The binding of sCD40L to CD40 on BJAB cells, an 51-negative B cell line, and the resulting activation of ERK1/2 was not inhibited by soluble 51, suggesting that sCD40L can bind concomitantly to both receptors. These results document the existence of novel CD40L-dependent pathways of physiological relevance for cells expressing multiple receptors (CD40, 51, and IIb3) for CD40L.

Received for publication, August 31, 2006 , and in revised form, November 27, 2006.

^* This work was supported in part by grants from the Arthritis Society of Canada, the Canadian Arthritis Network, and the Canadian Institutes of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Supported by a postdoctoral fellowship from the Fonds de la Recherche en Santé du Québec.

³ To whom correspondence should be addressed: Centre Hospitalier de l'Université de Montréal, Campus St. Luc, Pavillon Edouard-Asselin, 264 boulevard René Lévesque Est, Montréal, Quebec H2X 1P1, Canada. Tel.: 514-890-8000 Ext. 35287; Fax: 514-412-7314; E-mail: MW.Mourad{at}umontreal.ca.

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