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Regulation of Transforming Growth Factor-ß1 Expression by Granulocyte Macrophage-Colony-Stimulating Factor in Leiomyoma and Myometrial Smooth Muscle Cells

Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida 32610

Address all correspondence and requests for reprints to: Dr. Nasser Chegini, Department of Obstetrics and Gynecology, Box 100294 JHMHC, Gainesville, Florida 32610. E-mail: cheginin{at}obgyn.med.ufl.edu

Human myometrium and leiomyomas express granulocyte macrophage-colony-stimulating factor (GM-CSF), transforming growth factor-ß (TGFß), and their receptors. Overexpression of TGFß and, to a limited extent, GM-CSF has been associated with tissue fibrosis throughout the body, including leiomyomas. The objective of the present study was to determine the action of GM-CSF on leiomyoma and myometrial smooth muscle cells (LSMC and MSMC) and examine whether the action of GM-CSF is mediated through the induction of TGFß1 expression. Using competitive quantitative RT-PCR and enzyme-linked immunosorbent assay, we found that LSMC express significantly higher GM-CSF messenger ribonucleic acid (mRNA; 0.6 ± 0.1 x 10³ copies of mRNA/µg total RNA) and protein (0.75 ± 0.2 ng/mL) than MSMC (0.5 ± 0.1 x 10² copies of mRNA and 0.45 ± 0.07 ng/mL protein; P < 0.05). In addition, LSMC expressed significantly higher TGFß1 mRNA (1.6 ± 0.3 x 10⁴ copies of mRNA/µg total RNA) than MSMC (2.4 ± 0.4 x 10³ copies) and synthesized and secreted more TGFß1 protein (1.7 ± 0.2 vs. 0.5 ± 0.02 ng/mL); whereas MSMC contained more cell-associated TGFß1 (56.2 ± 1.2 ng/mL) than LSMC (35.2 ± 1.2 ng/mL; P < 0.05). We found that GM-CSF (0.01–100 ng/mL) has limited mitogenic activity for LSMC but not for MSMC determined by the rate of [³H]thymidine incorporation and cell proliferation assay. However, GM-CSF at 1 ng/mL increased its own production, the expression of TGFß1 mRNA, the cell-associated TGFß1 protein content in both cell types, and TGFß1 released into the culture-conditioned medium of LSMC (P < 0.05). TGFß1 also increased its own mRNA and protein expression, but had no effect on cell-associated TGFß1 in both cell types (P < 0.05). Cotreatment of LSMC and MSMC with GM-CSF and TGFß1 induced changes similar to those produced by GM-CSF in both cells. In conclusion, our data suggest that GM-CSF is not a mitogen for MSMC and LSMC, but it regulates its own expression and the expression of TGFß1 by these cells, a regulatory interaction that may account for the GM-CSF-induced tissue fibrosis that occurs in leiomyomas.

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