Regulation of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor expression by oncostatin M.
Oncostatin M (OM) is structurally and functionally related to a subclass of hematopoietic cytokines including leukemia-inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), granulocyte colony-stimulating factor (G-CSF), and interleukin-6 (IL-6). Using human endothelial cells (HEC) as a model for cytokine regulation of hematopoietic growth factor expression, we tested OM as an inducer of colony-stimulating activity. Colony-forming cell assays supplemented with culture supernatants from OM-treated HEC contained a threefold increase in colony-forming unit granulocyte-macrophage colonies. Specific immunoassay (enzyme-linked immunosorbent assay) of culture supernatants indicated that OM treatment of HEC resulted in a dose- and time-dependent increase in the accumulation of G-CSF and granulocyte-macrophage CSF (GM-CSF) (> 28-fold). The ED50 for OM induction of G-CSF and GM-CSF protein expression was 17 and 7 pmol/L, respectively. Increased protein expression was associated with a similar increase in steady-state expression of G-CSF and GM-CSF mRNA. Furthermore, a period of 12 to 24 hours elapsed before there were measurable increases in CSF expression, suggesting that OM may stimulate CSF production through a mechanism requiring the synthesis or activation of a secondary mediating factor or pathway. These findings provide the first evidence that OM may regulate myelopoiesis by inducing the cellular expression of hematopoietic growth factors.
Brown
T J
TJ
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA.
Liu
J
J
Brashem-Stein
C
C
Shoyab
M
M
D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004730:Endothelium, Vascular / Q000378:metabolism*; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors
C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D053683:Oncostatin M; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor