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Human marrow stromal cells: response to interleukin-6 (IL-6) and control of
IL-6 expression
J Nemunaitis, DF Andrews, DY Mochizuki, MB Lilly and JW Singer
Medical Service, Veterans Administration Medical Center, Seattle, WA 98108.
Production of interleukin-6 (IL-6) by marrow stromal cells from human
long-term marrow cultures and from stromal cells transformed with simian
virus 40 was examined. As with other cultured mesenchymal cells,
unstimulated stromal cells produced undetectable amounts of IL-6 mRNA when
assayed by Northern blots. However, within 30 minutes after exposure of
transformed marrow stromal cells to the inflammatory mediators, recombinant
human interleukin-1 alpha (IL-1 alpha) or recombinant human tumor necrosis
factor alpha (TNF alpha), significant increases in IL-6 expression were
observed. The time course of IL-6 mRNA upregulation in transformed marrow
stromal cells with IL-1 alpha and TNF alpha differed: The maximal response
to TNF alpha was observed at 30 minutes whereas that to IL-1 alpha occurred
at 8 hours. Although IL-6 at a concentration of 500 U/mL was inhibitory to
adherent transformed marrow stromal cell proliferation, a concentration-
dependent stimulation of anchorage-independent colony growth was observed
when the cells were plated in semisolid medium with IL-6. The stromal cell
colony-stimulating effect of IL-6 was abrogated by a neutralizing antibody
to IL-6. Moreover, the heteroserum with anti-IL-6 activity and two
anti-IL-6 monoclonal antibodies partially blocked autonomous and IL-1
alpha-induced colony formation, suggesting that colony formation by
transformed marrow stromal cells may require IL-6. Clonal-transformed
stromal cell lines were derived from the anchorage- independent stromal
cell colonies. Both IL-6 mRNA and protein were constitutively produced at
high levels. The addition of IL-6 to either long-term marrow culture
adherent cells or transformed marrow stromal cells downregulated the
expression of collagen I, a major stromal cell matrix protein. Thus, IL-6
affects proliferation of stromal cells and influences their production of
extracellular matrix, suggesting that IL- 6 may have indirect as well as
direct influences on hematopoietic cell proliferation.
Volume 74,
Issue 6,
pp. 1929-1935,
11/01/1989
Copyright © 1989 by The American Society of Hematology
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