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Articles |
Stimulates Proliferation of Rat Ovarian Theca-Interstitial Cells1
a Karol Marcinkowski University of Medical Sciences, Department of Gynecology and Obstetrics, 60-535 Poznan, Poland
b Yale University School of Medicine, Department of Obstetrics and Gynecology, New Haven, Connecticut 06520-8063
Tumor necrosis factor-
(TNF-
) is a potent modulator of ovarian function, affecting steroidogenesis of both granulosa and theca-interstitial (T-I) cells. Women with polycystic ovary syndrome (PCOS) have increased levels of serum TNF-
. The present study evaluated the effects of TNF-
on T-I cell proliferation. Purified rat T-I cells were cultured for 48 h with or without TNF-
(0.0011 nM), insulin-like growth factor I (IGF-I; 10 nM), and/or insulin (10 nM). Proliferation was measured by [3H]thymidine incorporation assay and by counting the steroidogenically active (stained positive for 3ß-hydroxysteroid dehydrogenase; 3ß-HSD) and inactive (3ß-HSD negative) cells. TNF-
stimulated thymidine incorporation in a dose-dependent fashion (up to 3.2-fold; P < 0.01). Insulin and IGF-I stimulated T-I proliferation (respectively, by up to 2.4- and 3.1-fold; P < 0.001). TNF-
potentiated effects of insulin and IGF-I in a dose-dependent and additive fashion (up to 6.7-fold; P < 0.001). TNF-
(1 nM) increased total cell count (by 80%, P < 0.05) and the proportion of 3ß-HSD-positive cells (by 19%, P < 0.05). Flow cytometry DNA analysis revealed that TNF-
(1 nM) increased the proliferative index by up to 16% (P = 0.05). The present findings demonstrate that TNF-
stimulates mitotic activity of T-I cells by increasing the proportion of actively dividing cells and preferentially increasing the number of steroidogenically active cells. The effects of TNF-
appear to be independent of those induced by insulin and IGF-I. We postulate that TNF-
may play a pathophysiologic role in disorders of the T-I compartment, such as PCOS.
2 Correspondence: Antoni J. Duleba, Yale University School of Medicine, Department of Obstetrics and Gynecology, 333 Cedar Street, New Haven, CT 06520. FAX: 203 785 7134; antoni.duleba{at}yale.edu
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