REGULATION OF THE EXPRESSION OF AMINOPEPTIDASE-A, AMINOPEPTIDASE N CD13 AND DIPEPTIDYLPEPTIDASE IV/CD26 IN RENAL-CARCINOMA CELLS AND RENAL TUBULAR EPITHELIAL-CELLS BY CYTOKINES AND CAMP-INCREASING MEDIATORS/

Aminopeptidase (AP) A is a transmembrane type II molecule widely distr ibuted in mammalian tissues. Since APA expression may be absent in ren al cell carcinoma (RCC), it is possible that there is an altered regul ation or other defect of APA upon malignant transformation of proximal tubular cells. However, investigations into the regulation of APA on tumour cells are rare. We report, for the first time, that both transf orming growth factor-beta 1 (TGF-beta 1) and tumour necrosis factor-al pha (TNF-alpha) down-regulate APA mRNA as well as protein expression i n renal tubular epithelial cells and RCC cells in culture. In addition to this, both cytokines decrease dipeptidylpeptidase (DP) IV/CD26 mRN A, but not APN/CD13 mRNA expression. Otherwise, IL-4 and IL-13 increas e CD13 as well as CD26 expression, but do not alter APA expression. In terferon-alpha (IFN-alpha), IFN-beta and IFN-gamma increase mRNA expre ssion of all the three membrane ectopeptidases, whereas LL-I, IL-6, IL -7, IL-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF ) have been found to be without any significant effect. Treatment of c ultured cells with cAMP-increasing agents, such as 8-bromo-cAMP or A23 187, results in an increase in APA and DPIV/CD26, but no change in APN /CD13 mRNA expression or even a decrease in it. Furthermore, AP inhibi tors can influence APA mRNA expression, since bestatin causes an incre ase in APA expression in a time-and dose-dependent manner, whereas bes tatin does not change CD13 or CD26 expression. No difference could be found with respect to the modulation by different mediators between RC C cells and renal epithelial cells, though permanent tumour cell lines such as Caki-1 and Caki-2 may have lost some of the normally expresse d peptidases.