EFFECTS OF WORTMANNIN AND RAPAMYCIN ON CSF-1 MEDIATED RESPONSES IN MACROPHAGES

There are differing views regarding the roles of phosphatidylinositol 3-kinases (PI3-kinases) and p70 S6 kinase (p70(s6k)) in growth factor- induced cellular responses. One approach that is widely employed to in vestigate these roles is to use the inhibitors, wortmannin and rapamyc in, respectively. This approach is used here to study the responses in macrophages to colony stimulating factor-1 (CSF-1). Wortmannin (great er than or equal to 30nM) and rapamycin (greater than or equal to 3 nM ) both weakly inhibited CSF-l-stimulated DNA synthesis in murine bone marrow-derived macrophages (BMM), suggesting that there are PI3-kinase - and p70(s6k)-independent pathways required for the onset of S phase; interestingly the combination of the drugs gave dramatic suppression. Inhibition of DNA synthesis by rapamycin on the BMM was much less tha n that observed with the CSF-l-dependent cell line, BAC1.2F5. In BMM, wortmannin suppressed CSF-l-stimulated increase in p70(s6k) activity i ndicating that PI3-kinase activity may lie upstream. In contrast to so me other growth factor/cell systems, no evidence was obtained using th e inhibitors for the involvement of PI3-kinase or p70(s6k) in, CSF-l-m ediated induction of c-fos mRNA expression or Erk-1 activity; in addit ion, no evidence was found for an involvement in the CSF-l-mediated in crease in cyclin D1 expression or STAT activation. The Endings reinfor ce the need to study the signal transduction cascades relevant to each individual growth factor and preferably not in cell lines. (C) 1998 P ublished by Elsevier Science Ltd. All rights reserved.