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IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro

2008; Elsevier BV; Volume: 111; Issue: 9 Linguagem: Inglês

10.1182/blood-2007-07-099531

1528-0020

Aruna Gowda, Julie M. Roda, Syed-Rehan A. Hussain, Asha Ramanunni, Trupti Joshi, S. Schmidt, Xiaoli Zhang, Amy Lehman, David Jarjoura, William E. Carson, Wayne Kindsvogel, Carolyn Cheney, Michael A. Caligiuri, Susheela Tridandapani, Natarajan Muthusamy, John C. Byrd,

Lymphoma Diagnosis and Treatment

Abstract Interleukin-21 (IL-21) is a recently identified γ-chain receptor cytokine family member that promotes B-cell apoptosis as well as activation of innate immune system. Based on this, we hypothesized that IL-21 might enhance the apoptosis induced by fludarabine and rituximab and also play a role in augmenting immune-mediated clearance of the chronic lymphocytic leukemia (CLL) cells. Our studies demonstrate that the majority of CLL patients have surface IL-21 receptor-α, and its expression correlates with apoptosis, tyrosine phosphorylation of STAT1, and up-regulation of the proapoptotic BH3 domain protein BIM. IL-21–induced BIM up-regulation is critical for apoptosis because inhibition of BIM expression using small interfering RNA prevented IL-21–induced apoptosis. IL-21 treatment of CLL cells but not normal T cells with fludarabine or rituximab additively enhanced the direct cytotoxic effect of these therapies. In addition to its proapoptotic effect, IL-21 promoted STAT1 and STAT5 phosphorylation in natural killer cells with concurrent enhanced antibody-dependent cellular cytotoxicity against rituximab-coated CLL cells in vitro. These data provide justification for combination studies of IL-21 with fludarabine and rituximab in CLL and suggest that BIM up-regulation might serve as relevant pharmacodynamic end point to measure biologic effect of this cytokine in vivo.