Suppression of G-CSF-mediated Stat signalling by IL-3.
G-CSF-induced myeloid differentiation of 32Dcl3 murine myeloblast cells is antagonized by concurrent exposure to interleukin-3 (IL-3) or by oncogenic transformation of 32Dcl3 by src- or abl-oncogenes which render the cells IL-3-independent. Recent reports have linked G-CSF-mediated differentiation to the ability of G-CSF to activate Stat3. We hypothesized that IL-3 suppresses 32Dcl3 differentiation in part through disruption of G-CSF-Stat signalling. We report that IL-3 inhibited the ability of G-CSF to induce Stat3 DNA binding. Moreover, we find that G-CSF activation of Stat3 binding to DNA is biphasic, peaking at 15-30 min and again at 6-8 h; both peaks are inhibited by IL-3. Transformation of 32Dcl3 cells by the v-abl oncogene leads to constitutive Stat3 activation and distinctive Stat-DNA-binding patterns which are not affected by G-CSF. Cross-modulation of Stat pathway signalling could be a physiologic mechanism for establishing a hierarchy of growth factor effects upon a cell exposed at once to multiple cytokines.
Steinman
R A
RA
University of Pittsburgh Cancer Institute, and Division of Hematology-Oncology, University of Pittsburgh School of Medicine, PA 15213, USA.
Iro
A
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D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D019319:Okadaic Acid / Q000494:pharmacology; D017452:Receptors, IgG / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D007377:Interleukin-3; D017452:Receptors, IgG; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D019319:Okadaic Acid