Impaired anti-tumor cytotoxicity of macrophages from osteopontin-deficient mice.
Osteopontin (OPN) expression in tumors is associated with more aggressive tumor growth; however, several studies have suggested that OPN as a host protein can regulate tumor growth as well. OPN is produced by macrophages and T cells, and reportedly modifies macrophage function. Here, we have investigated the effect of OPN on macrophage function, and its role in host defense against tumor growth. OPN deficient (-/-) and wild-type (WT) peritoneal macrophages were assessed for their ability to mediate cytotoxicity of tumor cells. Thioglycollate-elicited peritoneal exudate cells (PEC) were stimulated in vitro with interferon-gamma and lipopolysaccharide. [(3)H]Thymidine-labeled ras-transformed tumor cells were then added and (3)H release and nitrite accumulation were measured. OPN -/- PEC exhibited as much as a 70% reduction in cytotoxicity as compared to WT PEC. Tumor cell OPN status, on the other hand, had little effect on the extent of cytotoxicity. Production of nitrite by the PEC correlated with their capacity to kill tumor cells. L-929 cells, which are relatively resistant to nitric oxide-induced cytotoxicity and sensitive to that effected by TNF-alpha, were killed equally well by wild-type and OPN-deficient PEC, suggesting that the effect of OPN is not mediated through TNF-alpha. No difference was seen in the cytotoxicity of resident macrophages from mice of different genotypes, indicating that the defect in the OPN-deficient macrophages may result from altered differentiation in vivo. In support of this idea, we show that the expression of the macrophage markers F4/80 in peritoneal cells and of Mac-2 in spleen cells is altered in OPN -/- mice as compared to WT. These data support the hypothesis that host-derived osteopontin may inhibit tumor growth and provide a mechanism for this effect.
Bourassa
Brenda
B
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
Monaghan
Sara
S
Rittling
Susan R
SR
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*
D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D009569:Nitric Oxide