The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways.
The clonal expansion of chronic lymphocytic leukemia (CLL) cells requires the interaction with the microenvironment and is under the control of several cytokines. Here, we investigated the effect of IL-15 and IL-21, which are closely related to IL-2 and share the usage of the common gamma chain and of its JAK3-associated pathway. We found remarkable differences in the signal transduction pathways activated by these cytokines, which determined different responses in CLL cells. IL-15 caused cell proliferation and prevented apoptosis induced by surface IgM cross-linking. These effects were more evident in cells stimulated via surface CD40, which exhibited increased cell expression of IL-15Ralpha chain and, in some of the cases, also of IL-2Rbeta. IL-21 failed to induce CLL cell proliferation and instead promoted apoptosis. Following cell exposure to IL-15, phosphorylation of STAT5 was predominantly observed, whereas, following stimulation with IL-21, there was predominant STAT1 and STAT3 activation. Moreover, IL-15 but not IL-21 caused an increased phosphorylation of Shc and ERK1/2. Pharmacological inhibition of JAK3 or of MEK, which phosphorylates ERK1/2, efficiently blocked IL-15-induced CLL cell proliferation and the antiapoptotic effect of this cytokine. The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention.
de Totero
Daniela
D
Department of Translational Oncology and Medical Oncology C, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Meazza
Raffaella
R
Capaia
Matteo
M
Fabbi
Marina
M
Azzarone
Bruno
B
Balleari
Enrico
E
Gobbi
Marco
M
Cutrona
Giovanna
G
Ferrarini
Manlio
M
Ferrini
Silvano
S
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D007152:Immunologic Capping / Q000187:drug effects / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology* / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology; D053646:Interleukin-2 Receptor beta Subunit / Q000276:immunology; D007378:Interleukins / Q000276:immunology* / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D020930:MAP Kinase Kinase Kinases / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D053647:Receptors, Interleukin-15 / Q000276:immunology; D050791:STAT Transcription Factors / Q000276:immunology*; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000098546:Interleukin-21
D048868:Adaptor Proteins, Signal Transducing; C508024:IL15RA protein, human; C508020:IL2RB protein, human; C508025:Il15ra protein, mouse; C508022:Il2rb protein, mouse; D007075:Immunoglobulin M; D019409:Interleukin-15; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D007378:Interleukins; D053647:Receptors, Interleukin-15; C528024:SHC1 protein, human; D050791:STAT Transcription Factors; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; D000098546:Interleukin-21