IN-VIVO AND IN-VITRO EFFECTS OF MACROPHAGE-COLONY-STIMULATING FACTOR (M-CSF) ON BRONCHOALVEOLAR MACROPHAGES FOR ANTIHISTOPLASMAL ACTIVITY

The in vivo and in vitro effects of M-CSF on bronchoalveolar macrophag es (BAM) activity against the intracellular fungal pathogen Histoplasm a capsulatum (He) were studied. Three days after a single subcutaneous (s.c.) dose of M-CSF (2.5 mg/kg), enhanced ex vivo antifungal activit y of BAM was measured. BAM from M-CSF-treated CD-1 mice significantly (P<0.01) inhibited the intracellular multiplication of He yeast cells in 20 h assays compared to BAM from control mice. This effect was not observed at days 1, 7, 11 or 21 post-treatment. A dose of 5 mg/kg s.c. , but not 1 mg/kg, induced similar antifungal activity in BAM by day 3 . Peritoneal macrophages (PM) from M-CSF-treated mice did not have enh anced antifungal activity at days and doses tested. BAM could also be activated for antihistoplasmal activity by M-CSF in vitro. M-CSF at 10 ,000 U/ml for 24 h or 5000 U/ml for 48 h induced significant (P<0.01) inhibition of intracellular multiplication of He. Interferon-gamma (IF N) plus lipopolysaccharide (LPS) activated BAM and PM in vitro to inhi bit intracellular multiplication of He (P<0.001); the antihistoplasmal activity was completely inhibited by N-G-monomethyl L-arginine (N-MMA ), indicating that an L-arginine-dependent nitric oxide-producing mech anism was operative. N-MMA could not inhibit the antihistoplasmal acti vity of BAM or PM activated by M-CSF in vitro. The mechanism by which M-CSF-activated macrophages inhibit intracellular multiplication of He remains to be determined.