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Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1346-1354
Both Stat3-Activation and Stat3-Independent BCL2 Downregulation Are
Important for Interleukin-6-Induced Apoptosis of 1A9-M Cells
Kenji Oritani,
Yoshiaki Tomiyama,
Paul W. Kincade,
Keisuke Aoyama,
Takafumi Yokota,
Itaru Matsumura,
Yuzuru Kanakura,
Koichi Nakajima,
Toshio Hirano, and
Yuji Matsuzawa
From The Second Department of Internal Medicine, The Department of
Hematology/Oncology, and The Department of Molecular Oncology,
Biomedical Research Center, Osaka University Medical School, Osaka,
Japan; and the Oklahoma Medical Research Foundation, Oklahoma City, OK.
A unique subclone of a bone marrow-derived stromal cell line,
BMS2.4, produces soluble factors that inhibit proliferation of several
types of hematopoietic cell lines. An understanding of these molecules
may be informative about negative regulatory circuits that can
potentially limit blood cell formation. We used expression cloning to
identify interleukin-6 (IL-6) as one factor that suppressed growth of a
pre-B-cell variant line, 1A9-M. Moreover, IL-6 induced
macrophage-differentiation and apoptosis of 1A9-M cells. During this
process, IL-6 downregulated expression of BCL2 in 1A9-M cells and
stimulated BCL-XL expression, but had no effect on p53, Bax, or Bak
gene expression. Mechanisms for transduction of IL-6-induced signals
were then evaluated in IL-6-stimulated 1A9-M cells. Whereas the signal
transducer and activator of transcription 3 (Stat3) was phosphorylated
and activated, there was no effect on either Stat1 or Stat5. The
importance of BCL2 and Stat3 on IL-6-induced
macrophage-differentiation and apoptosis was studied with 1A9-M cells
expressing human BCL2 or a dominant-negative form of Stat3,
respectively. IL-6-induced apoptosis, but not
macrophage-differentiation, was blocked by continuously expressed BCL2.
A dominant-negative form of Stat3 inhibited both
macrophage-differentiation and apoptosis induced by IL-6. However,
diminished Stat3 activity did not prevent IL-6-induced downregulation
of the BCL2 gene. Therefore, activation of Stat3 is essential for
IL-6-induced macrophage-differentiation and programmed cell death in
this model. Whereas overexpression of BCL2 abrogates the apoptotic
response, Stat3-independent signals appear to downregulate expression
of the BCL2 gene.
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