INTERLEUKIN-7 REGULATES C-MYC EXPRESSION IN MURINE T-CELLS AND THYMOCYTES - A ROLE FOR TYROSINE KINASE(S) AND CALCIUM MOBILIZATION

Interleukin-7 (IL-7) was originally identified as a pre-B cell growth factor whose proliferating activity has been extended to numerous targ et cells including T lymphocytes. We investigated c-myc mRNA expressio n, an oncogene associated with proliferation, in the murine T cell lin e D10 G4.1 and freshly isolated thymocytes since both target cells pro liferate in response to IL-7. We find that blockade of the tyrosine ki nase pathway by genistein, a potent tyrosine kinase inhibitor, inhibit s both IL-7-dependent D10 G4.1 cell proliferation and c-myc mRNA expre ssion which appears to involve de note mRNA synthesis and to be under the control of short-lived protein repressor(s). We have also examined possible signal transduction pathways which might regulate c-myc mRNA expression in the murine T cell line. IL-7 biological activity is not affected by stimulation of the protein kinase C pathway by phorbol es ters. Thus, IL-7 regulates c-myc mRNA expression in a protein kinase C -independent manner and these data are strengthened by protein kinase C depletion which does not modify IL-7 c-myc mRNA responsiveness. In c ontrast and independent of protein kinase C activation, intracellular calcium mobilization by means of ionomycin reduces IL-7 induction of c -myc mRNA expression and may represent a physiological mechanism where by IL-7 bioactivity is regulated. The activity of IL-7 on c-myc mRNA e xpression has been extended to freshly isolated thymocytes and we find a synergistic effect of IL-7 with concanavalin A. Taken together our results illuminate the molecular mechanism of IL-7 c-myc induction in the T lineage by ascribing a role for tyrosine kinase and increase in intracellular calcium in both IL-7 induced gene induction and cell pro liferation.