Vitamin D-binding protein-macrophage-activating factor (
DBP-maf) is derived from serum
vitamin D binding protein (DBP) by selective deglycosylation during
inflammation. In the present study, we investigated the effect of
DBP-maf on RAW 264.7 macrophages and the underlying intracellular signal transduction pathways.
DBP-maf increased proapoptotic
caspase-3, -8, and -9 activities and induced apoptosis in RAW 264.7 cells. However, DBP, the precursor to
DBP-maf did not induce apoptosis in these cells. Cell cycle analysis of
DBP-maf-treated RAW 264.7 cells revealed growth arrest with accumulation of cells in sub-G(0)/G(1) phase. We also investigated the role of
mitogen-activated protein kinase (MAPK) pathways in the
DBP-maf-induced apoptosis of RAW264.7 cells.
DBP-maf increased the phosphorylation of p38 and JNK1/2, while it decreased the ERK1/2 phosphorylation. Treatment with the
p38 MAPK inhibitor,
SB202190, attenuated
DBP-maf-induced apoptosis.
PD98059, a
MEK specific inhibitor, did not show a significant inhibition of apoptosis induced by
DBP-maf. Taken together, these results suggest that the
p38 MAPK pathway plays a crucial role in
DBP-maf-mediated apoptosis of macrophages. Our studies indicate that, during
inflammation DBP-maf may function positively by causing death of the macrophages when activated macrophages are no longer needed at the site of
inflammation. In summary, we report for the first time that
DBP-maf induces apoptosis in macrophages via p38 and JNK1/2 pathway.