IL-6 inhibits apoptosis of human myeloma cell line XG-7 through activation of JAK/STAT pathway and up-regulation of Mcl-1.
OBJECTIVE
IL-6 can protect myeloma cells from apoptosis induced by various stimuli. A series of intracellular molecules might participate in this process. Our aim in this study is to investigate which anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-XL, Mcl-1) and which signal transduction pathway(JAK/STAT, Ras/MAPK, PI-3K/Akt) can mediate the anti-apoptotic effect of IL-6 on a human myeloma cell line XG-7.


METHODS
Apoptosis of XG-7 cells was analyzed by flow cytometry with propidium iodide(PI) staining of nuclei. The expression of three Bcl-2 family proteins in XG-7 cells were monitored by immunoblot assay. AG490, PD98059, and LY294002, three specific antagonists for JAK/STAT, Ras/MAPK, and PI-3K/Akt signal transduction pathways respectively, were used to determine which signal transduction pathway was responsible for the effect of IL-6 on XG-7 cells.


RESULTS
IL-6 inhibited the apoptosis of XG-7 cells and up-regulated the expression of only one of the three anti-apoptotic Bcl-2 family proteins-Mcl-1. In addition, up-regulation of Mcl-1 expression induced by IL-6 was significantly inhibited in the presence of AG490, while not of PD98059 and LY294002.


CONCLUSIONS
IL-6 inhibited apoptosis of XG-7 cells through up-regulation of Mcl-1 and the activation of JAK/STAT rather than Ras/MAPK nor PI-3K/Akt signal transduction pathway.
Song
Lun
L
Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100850, P. R. China. lunsong@yahoo.com
Li
Yan
Y
Sun
Ying-xun
YX
Yu
Ming
M
Shen
Bei-fen
BF
D017209:Apoptosis / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009101:Multiple Myeloma / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases