Autocrine regulation of Leydig cell differentiated functions by insulin-like growth factor I and transforming growth factor beta

The expression and the maintenance of specific differentiated function of L eydig cells are regulated not only by gonadotropin but by locally produced factors, which may act as autocrine regulators. Many factors, in particular growth factors, have been postulated to have such a type of effect on test icular cells, but very few fulfilled the three criteria required to establi sh a paracrine/autocrine role: (a) presence of receptors and biological act ion on local cells; (b) local secretion regulated by physiological signals; and (c) blockade of the factor or its receptors must modify the function o f local cells. In the present work we demonstrate that two factors, insulin -like growth factor 1 (IGF-I) and transforming growth factor beta 1 (TGF be ta 1) fulfilled the three criteria: (a) IGF-I stimulates the transcription of the genes encoding Leydig cell differentiated function, leading to an en hanced steroidogenic responsiveness to LH/hCG; (b) Leydig cells (LC) expres s and secrete IGF-I and this secretion is enhanced by hCG; and (c) incubati on of LC with IgG anti-IGF-I, but not with IgG-control, markedly reduced th e steroidogenic responsiveness to LH/hCG, In contrast to IGF-I, TGF beta is a potent inhibitor of LC differentiated function. Moreover, LC express TGF beta 1 mRNA and secrete this peptide. To prove that the locally produced T GF beta has an autocrine role, LC were transfected with 10 mu M of an antis ense oligonucleotide (AON) complementary to the translation initiation regi on of TGF beta 1 mRNA, Transfection with AON but not with sense deoxynucleo tide induces a complete disappearance of TGF beta immunoreactivity in LC an d an enhanced hCG-induced testosterone production by LC. This increased ste roidogenic responsiveness was associated with a significant enhancement of both LH/hCG receptor mRNA and P450c17 mRNA. Taken together, the above resul ts show that both factors play an autocrine role, although opposite, on Ley dig cell function. (C) 1999 Elsevier Science Ltd. All rights reserved.