Ha. Naama et al., Suppression of macrophage nitric oxide production by melanoma: mediation by a melanoma-derived product, MELANOMA RE, 11(3), 2001, pp. 229-238
The tumour-bearing state is known to induce immune dysfunction that contrib
utes to increased infectious complications and tumour progression. However,
the mechanisms underlying this immunosuppression remain unclear. This stud
y investigated in a murine model the effects of melanoma growth on nitric o
xide (NO) production by peritoneal macrophages in vivo and in vitro. B16 an
d K1735 melanoma cells were inoculated subcutaneously into C57BL/6 and G3H/
HeN mice, respectively. stimulated NO production by elicited peritoneal mac
rophages was examined in control and melanoma-bearing mice. An in vitro sys
tem was established to assess the effects of co-culturing melanoma cells (B
16 and K1735) or melanoma-conditioned medium with normal peritoneal macroph
ages on subsequent NO production. NO production was significantly suppresse
d in macrophages from melanoma-bearing mice. Co-culture of normal macrophag
es with melanoma cells in a transwell system or with melanoma-conditioned m
edia in vitro reproduced the defects observed in vivo without affecting mac
rophage viability, pointing to a melanoma-derived product as the basis for
the observed suppression of NO production. This inhibition required RNA and
protein synthesis and was dose and time dependent. Using inhibition profil
es and neutralizing antibodies, it was demonstrated that this melanoma inhi
bitory activity was distinct from known NO inhibitors. Preliminary characte
rization attributed this activity to a melanoma-secreted protein moiety. (C
) 2001 Lippincott Williams & Wilkins.