Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells.
Interleukin-21 (IL-21) is a member of the IL-2 cytokine family, which mediates proliferation or growth arrest and apoptosis of normal B cells, depending on their activation state. Here we demonstrate that surface IL-21 receptor (R) is expressed at variable levels by chronic lymphocytic leukemia (CLL) B cells freshly isolated from 33 different patients. IL-21R expression was up-regulated following cell stimulation via surface CD40. Therefore, IL-21 effects were more evident in CD40-activated CLL B cells. IL-21 induced an early signaling cascade in CLL B cells, which included JAK-1 and JAK-3 autophosphorylation and tyrosine phosphorylation of STAT-1, STAT-3, and STAT-5. IL-21 signaling failed to stimulate CLL B-cell proliferation, but induced their apoptosis. In addition, IL-21 counteracted the proliferative and antiapoptotic signals delivered by IL-15 to CLL B cells. IL-21-mediated apoptosis involved activation of caspase-8 and caspase-3, cleavage of Bid to its active form t-Bid, and cleavage of PARP and of p27Kip-1. Recent data indicate that CLL B cells require interaction with the microenvironment for their survival and expansion. The present findings thus provide a set of new mechanisms involved in the balance between cell-survival and apoptotic signals in CLL B cells.
de Totero
Daniela
D
Laboratory of Immunotherapy, IST c/o CBA Largo R. Benzi, 10, 16132 Genova, Italy.
Meazza
Raffaella
R
Zupo
Simona
S
Cutrona
Giovanna
G
Matis
Serena
S
Colombo
Monica
M
Balleari
Enrico
E
Pierri
Ivana
I
Fabbi
Marina
M
Capaia
Matteo
M
Azzarone
Bruno
B
Gobbi
Marco
M
Ferrarini
Manlio
M
Ferrini
Silvano
S
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D019013:CD40 Antigens / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D053738:Interleukin-21 Receptor alpha Subunit; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics*; D053655:Receptors, Interleukin-21; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D019013:CD40 Antigens; D004273:DNA, Neoplasm; C508117:IL21R protein, human; C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053655:Receptors, Interleukin-21; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3