Tumour necrosis factor-alpha stimulates proliferation of rat ovarian theca-interstitial cells

Tumor necrosis factor-alpha (TNF-alpha) is a potent modulator of ovarian fu nction, affecting steroidogenesis of both granulosa and theca-interstitial (T-I) cells. Women with polycystic ovary syndrome (PCOS) have increased lev els of serum TNF-alpha. The present study evaluated the effects of TNF-alph a on T-I cell proliferation. Purified rat T-I cells were cultured for 48 h with or without TNF-alpha (0.001-1 nM), insulin-like growth factor I (IGF-I ; 10 nM), and/or insulin (10 nM). Proliferation was measured by [H-3]thymid ine incorporation assay and by counting the steroidogenically active (stain ed positive for 3 beta-hydroxysteroid dehydrogenase; 3 beta-HSD) and inacti ve (3 beta-HSD negative) cells. TNF-alpha stimulated thymidine incorporatio n in a dose-dependent fashion (up to 3.2-fold; P < 0.0z1). Insulin and IGF- I stimulated T-I proliferation (respectively, by up to 2.4- and 3.1-fold; P < 0.001). TNF-alpha potentiated effects of insulin and IGF-I in a dose-dep endent and additive fashion (up to 6.7-fold; P < 0.001). TNF-alpha (1 nM) i ncreased total cell count (by 80%, P < 0.05) and the proportion of 3 beta-H SD-positive cells (by 19%, P < 0.05). Flow cytometry DNA analysis revealed that TNF-alpha (1 nM) increased the proliferative index by up to 16% (P = 0 .05). The present findings demonstrate that TNF-alpha stimulates mitotic ac tivity 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-alpha appear to be independent of those induced by ins ulin and IGF-I. We postulate that TNF-alpha may play a pathophysiologic rol e in disorders of the T-I compartment, such as PCOS.