AbstractComplex patterns of metabolic and functional characteristics are induced in macrophages by biological response modifiers. The study of the early events resulting from the transduction of immunomodulatory signals could be an approach for a better understanding of this activation process. The transcription of c-fos and c-myc genes has been shown to be rapidly modified in many cells responding to various signals. Since murine peritoneal macrophages are a rather heterogeneous population we chose to investigate the c-fos and c-myc modulation in the P388D1 murine macrophage line. Owing to the frequent implication of the c-myc gene in the tumorigenicity of hematopoietic cells we first demonstrated the normal c-myc status in this cell line by Southern analysis. The modulation of the c-fos and c-myc expression has been studied by Northern analysis, 15, 30 and 60 minutes after treatment of the P388D1 cells by the phorbol ester (TPA), the Calcium ionophore A 23187 (Ca2+I), the N-acetyl muramyldipeptide (MDP) or the macrophage Colony Stimulating Factor (CSF-1). The mitogenic activity of these compounds, as evaluated by pH] thymidine incorporation, has been measured either after a 30 minute or a 24 hour treatment.An early increase in c-fos expression always preceded a c-myc augmentation. The highest modulation of c-fos and c-myc was observed with TPA. Ca2+I and TPA presented a low mitogenic effect if compared to CSF-1. MDP did not change DNA synthesis even after 24 hours. Therefore, in the present study on the P388D1 macrophage cell line, no direct correlation could be evidenced between the mitogenic effect and the modulation of c-fos and c-myc induced by these immunomodifiers. Investigations are in progress in order to evaluate the role of these proto-oncogenes on terminal differentiation induced by immunomodulators in this cell line.