1 UMRS 872 INSERM/University Pierre et Marie Curie/University Paris Descartes, Team 18, France
2 Plateau d’Imagerie Cellulaire, Centre de Recherche des Cordeliers, Paris, France
CLL cells are resistant in vivo to apoptosis, in part, through the autocrine action of the survival factors BAFF and APRIL. We show here, by flow cytometry, that stimulation of Toll-like receptor-7 (TLR-7) with imidazoquinolines induces increases in the expression by CLL cells of BAFF, APRIL and their receptors, results confirmed by Western blot. Moreover, sBAFF and sAPRIL released by leukemia cells are increased in supernatants from Resiquimod-treated cells. These events correlated with an increased resistance against apoptosis, both APRIL and BAFF contributing to this protection. Ligation of TLR-7 activated the canonical and alternative pathways of NFκB activation. An inhibitor of I κBa phosphorylation largely prevented these effects. Addition of Resiquimod to CLL cells also elicited the activation of several members of the AP-1 family, notably phosphorylation of c-Jun, and the protection against apoptosis was mostly reverted with a specific inhibitor of JNK.
TLR-7 signaling therefore stimulates apoptosis resistance through activation of the BAFF/APRIL pathways. TLR-7 may be activated in vivo by PAMPs (pathogen-associated molecular patterns) of microorganisms and/or antigens expressed by cells undergoing apoptosis, as already reported for stimulation of the BCR in CLL cells. The engagement of TLRs could be involved in the aetiology of CLL.
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