title: 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.
abstract: Interleukin-21 (IL-21) is a recently identified gamma-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-alpha, 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.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, The Ohio State University, Columbus, USA.
authors.forename: Aruna
authors.initials: A
authors.lastname: Gowda
authors.forename: Julie
authors.initials: J
authors.lastname: Roda
authors.forename: Syed-Rehan A
authors.initials: SR
authors.lastname: Hussain
authors.forename: Asha
authors.initials: A
authors.lastname: Ramanunni
authors.forename: Trupti
authors.initials: T
authors.lastname: Joshi
authors.forename: Susan
authors.initials: S
authors.lastname: Schmidt
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.forename: Wayne
authors.initials: W
authors.lastname: Kindsvogel
authors.forename: Carolyn
authors.initials: C
authors.lastname: Cheney
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000069283:Rituximab; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D000098546:Interleukin-21
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D007378:Interleukins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; D000069283:Rituximab; D014740:Vidarabine; D000098546:Interleukin-21; C024352:fludarabine