JAK pathway induction of c-Myc critical to IL-5 stimulation of cell proliferation and inhibition of apoptosis.
Interleukin-5 (IL-5) induction of c-Myc expression is associated with IL-5 inhibition of apoptosis in hematopoietic cells. In this study, TFalpha1 and TFalpha8 cells with stable overexpression of IL-5 receptor alpha (IL-5Ralpha) subunit in TF-1 cells, a human hematopoietic progenitor cell line which expressed low levels of IL-5Ralpha, were used to explored how IL-5 up-regulate c-Myc and the role of c-Myc in IL-5 signaling. First, we demonstrate that IL-5 induced c-Myc RNA and protein expressions, as well as activated Janus kinases (JAK1 and JAK2) and signal transducer and activator of transcription-5b (STAT5b). JAK inhibitor AG490 and c-Myc inhibitor 10058-F4, both, reduced IL-5-mediated cell proliferation in a dose- and time-dependent manner. Both, AG490 and 10058-F4, also reduced IL-5-mediated anti-apoptotic activity. Furthermore, AG490 inhibited IL-5-mediated c-Myc induction and promoter activity. We further examined the role of JAK1 and JAK2 in the induction of c-Myc expression using the CDJAK fusion proteins, which consisted of a CD16 extracellular domain, a CD7 transmembrane domain, and either JAK1 (CDJAK1) or JAK2 (CDJAK2) as intracellular domains. Simultaneous activation of JAK1 and JAK2 by anti-CD16 antibody crosslinking of CDJAK1 and CDJAK2 could induced c-Myc expression and promoter activity; AG490 inhibited CDJAK1 and CDJAK2-mediated effects. These results suggest that IL-5 induces cell proliferation and anti-apoptosis through the JAK/c-Myc pathway, and that JAK1 and JAK2 activation participate in IL-5-induced up-regulation of c-Myc.
Lee
Wei-Hwa
WH
Department of Laboratory Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
Liu
Fu-Hwa
FH
Lin
John Yi-Chung
JY
Huang
Shih-Yun
SY
Lin
Heng
H
Liao
Wei-Ju
WJ
Huang
Huei-Mei
HM
D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015848:Interleukin-5; D053613:Janus Kinase 1 / Q000378:metabolism / Q000502:physiology; D053614:Janus Kinase 2 / Q000378:metabolism / Q000502:physiology; D053612:Janus Kinases / Q000378:metabolism / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000235:genetics
D015848:Interleukin-5; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053612:Janus Kinases