A. Jaworowski et al., Roles of the mitogen-activated protein kinase family in macrophage responses to colony stimulating factor-1 addition and withdrawal, J BIOL CHEM, 274(21), 1999, pp. 15127-15133
Colony stimulating factor-1 (CSF-1) (or macrophage CSF) is involved in the
survival, proliferation, differentiation, and activation of cells of the mo
nocyte/macrophage lineage. Because the mitogen-activated protein kinase fam
ily members extracellular signal-regulated kinases (ERKs), p38, and c-Jun N
-terminal kinase are widely implicated in such cellular functions, we measu
red their activity in growing and growth-arrested cultures of bone marrow-d
erived macrophages (BMM), as well as their stimulation by saturating concen
trations of CSF-1, ERK activity was approximately a-fold higher in cycling
BMM compared with growth-arrested BMM; in addition, CSF-l-stimulated BMM DN
A synthesis was partially inhibited by PD98059, a specific inhibitor of MEK
activation, suggesting a role for a mitogen-activated protein-ERK kinase (
MEK)/ERK pathway in the control of DNA synthesis but surprisingly not in th
e control of cyclin D1 mRNA or c-myc mRNA expression. The suppression of BM
M apoptosis by CSF-1, i.e, enhanced survival, was not reversed by PD98059,
suggesting that a MEK/ERK pathway is not involved in this process.
Using a quantitative kinase assay, it was found that CSF-1 gave a slight in
crease in BMM p38 activity, supporting prior data that CSF-1 is a relativel
y weak stimulator of inflammatory cytokine production in monocytes/macropha
ges, Relatively high concentrations of the p38 inhibitor, SKB202190, suppre
ssed CSF-l-stimulated BMM DNA synthesis. No evidence could be obtained for
the involvement of p38 activity in BMM apoptosis following CSF-1 withdrawal
. We were not able to show that CSF-1 enhanced BMM JNK-1 activity to a sign
ificant extent; again, no role could be found for JNK-1 activity in the BMM
apoptosis occurring after CSF-1 removal.