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Tumor Necrosis Factor- Regulates Plasminogen Activator Inhibitor-1 in Rat Testicular Peritubular Cells¹

INSERM U-407, Bâtiment 3B, Centre Hospitalier Lyon-Sud, Pierre-Benite; and Laboratoire d’ Hématologie, Centre Hospitalo-Universitaire La Tronche (G.P., L.K.), Grenoble, France

Address all correspondence and requests for reprints to: Dr. Brigitte Le Magueresse-Battistoni, INSERM U-407, Bâtiment 3B, Centre Hospitalier Lyon-Sud, 69495 Pierre-Bénite Cedex, France.

We examined the regulation by tumor necrosis factor- (TNF) of plasminogen activator inhibitor-1 (PAI-1) in cultured peritubular cells recovered from 20-day-old rat testes. We demonstrated that TNF in a nanomolar dose range stimulated PAI-1 messenger RNA (mRNA; Northern blots) as well as immunoreactive (Western blots) and bioactive (Stachrom) PAI-1 protein. Induction of PAI-1 mRNA started 4 h after the addition of TNF (2.5-fold increase) and peaked (7-fold increase) after 24 h of treatment. Actinomycin D and cycloheximide inhibited the effects of TNF on PAI-1 mRNA, suggesting that ongoing RNA and protein syntheses were required. The combined actions of transforming growth factor- (TGF), a potent inducer of PAI-1, and TNF on PAI-1 were less than additive, suggesting the activation of some common pathway. TNF action on PAI-1, like that of TGF demonstrated previously, was masked by a preexposure to phorbol myristate acetate (a stimulator of protein kinase C) and strongly reduced by staurosporine (an inhibitor of the protein kinase C). Furthermore, using genistein to inhibit tyrosine kinase activity, we not only blocked the action of TGF on PAI-1 [initiated upon binding to the tyrosine kinase epidermal growth factor/TGF receptor (EGFR)], but also markedly reduced that of TNF. Finally, TNF, at a dose range that stimulated PAI-1, enhanced EGFR mRNA levels and EGF binding. Together, the present findings suggest that some of the biological effects of TNF on PAI-1 might be secondary to de novo synthesis of EGFR. Because TNF probably originates from testicular macrophages, such a regulation of PAI-1 by TNF may occur in the context of physiological interactions between the testis and the immune system.

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