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 target cells including T lymphocytes. We investigated c‐myc mRNA expression, an oncogene associated with proliferation, in the murine T cell line D10 G4.1 and freshly isolated thymocytes since both target cells proliferate in response to IL‐7. We find that blockade of the tyrosine kinase pathway by genistein, a potent tyrosine kinase inhibitor, inhibits both IL‐7‐dependent D10 G4.1 cell proliferation and c‐myc mRNA expression which appears to involve de novo 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 esters. 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 contrast 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 whereby IL‐7 bioactivity is regulated. The activity of IL‐7 on c‐myc mRNA expression 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 proliferation.