Primary Response Gene Induced by Interleukin 6 and Leukemia Inhibitory Factor: Role in Growth Inhibition’

To better understand the immediate early genetic response of myeboid cells to terminal differentiation and growth inhibitory stimuli, we have recently isolated complementary DNA clones of myeboid differentiation primary response (MyD) genes, activated in the absence of protein synthesis in Ml myeboid precursor cells following induction for terminal differentiation and growth arrest by conditioned media of mouse lungs, a potent physiological source of hemopoietic differentiation inducers. In this study, it is shown that one particular MyD complementary DNA clone, expressed highly in normal precursor enriched bone marrow cells, encodes for interferon regulatory factor 1 (IRF-1), a positive transcription factor for expression of the j9-interferon (IFN-) gene. Using a clone of Ml cells inducible for terminal differentiation by both interleukin 6 (IL-6) and leukemia inhibitory factor (LIF), two multifunctional cytokines recently identified as physiological inducers of hemopoietic cell differentiation, it has been shown that IRF- 1 expression is rapidly induced by IL-6 and LIF in the absence of protein synthesis and is followed by a later increase in the bevels of IFN- $ mRNA, observed to be largely dependent on protein synthesis. Also, it is shown that the growth inhibition associated with IL-6 or LIF induced terminal differentiation could be partially abrogated via the use of IRF-l antisense oligomers or IFN-fl antiserum. Taken together, these findings imply a regulatory cascade, where induction of terminal myeloid differentiation by IL-6 or LIF triggers the immediate early activation of IRF-l, leading to the later induction of IFN-fi, in turn playing an autocrine robe in growth inhibition