ENDOGENOUS IFN-ALPHA-BETA SUPPRESSES COLONY-STIMULATING FACTOR (CSF)-1-STIMULATED MACROPHAGE DNA-SYNTHESIS AND MEDIATES INHIBITORY EFFECTS OF LIPOPOLYSACCHARIDE AND TNF-ALPHA

Murine bone marrow-derived macrophages (BMM) are widely used as a suit able model to study the proliferative response to macrophage-CSF or CS F-1. We report here that the amount of DNA synthesis observed in BMM c ultures in response to CSF-1 can be masked quite significantly by low levels of IFN-alpha beta produced in the cultures, It was found that A b to IFN-alpha beta could enhance the proliferative response in CSF-tr eated BMM that were able to respond to endogenous IFN-alpha beta; howe ver, BMM from mice lacking a component of the type I IFN receptor did not show any enhancement of CSF-l-dependent DNA synthesis on addition of the Ab, While DNA synthesis in CSF-1-stimulated BMM from normal mic e was also very sensitive to the inhibitory actions of very low concen trations of added IFN-alpha beta, DNA synthesis in BMM from the ''knoc kout'' mice was not, indicating that the type I IFN receptor component containing the null mutation was essential for signal transduction, P reviously it was shown that bacterial LPS, TNF-alpha, IFN-gamma, and c AMP could all inhibit CSF-1-stimulated BMM DNA synthesis and prolifera tion, Using the combined approach of blocking IFN-alpha beta Ab and th e IFN receptor ''knockout'' mice, it was found here that the growth-in hibitory effects of LPS and TNF-alpha are due, to a significant extent , to endogenous IFN-alpha beta, whereas those of IFN-gamma and cAMP oc cur by a different mechanism, It is proposed that the type I IFN recep tor (IFNAR 1) ''knockout'' mice may be useful in delineating some of t he in vivo actions of CSF-1, LPS, TNF-alpha, and possibly other agents .