The altered tumoricidal capacity of macrophages isolated from tumor-bearing mice is related to reduce expression of the inducible nitric oxide synthase gene.

Abstract

SummaryNitric oxide (NO) is a major effector molecule in the destruction of tumor cells by activated macrophages. However, in many cases, developing neoplasms appear to be capable of impairing steps in the complex process leading to NO production as a means of avoiding immune destruction. After activation with lipopolysaccharide (LPS), peritoneal-ehcited macrophages (PEM) from mice bearing mammary tumors display alterations in their ability to lyse tumor cells due to reduced production of NO. In contrast, when these same cells are stimulated with LPS in combination with interferon ~/(IFN-~/), they are able to produce NO and lyse targets at normal levels. Since tumor-associated macrophages are intimately associated with the cells of the developing tumor, their ability to produce NO and lyse tumor targets is likely to be more relevant to controlling tumor growth. This population of macrophages exhibited a more profound inability to produce NO and lyse targets and, unlike the PEM, was not able to upregulate these functions even when treated with combinations of LPS and IFN-~. Northern and Western blots revealed that inducible nitric oxide synthase (iNOS) mRNA and protein levels correlated directly with the ability of each macrophage population to produce NO, and the levels of these macromolecules were altered sufficiently in tumor bearers' macrophages to account for the diminished NO production described. These results indicate that a spatial gradient of suppression of macrophage cytolytic activity and iNOS expression exists in mammary tumor-bearing mice, whereby macrophages from within the tumor exhibit a more pronounced suppression than the more distally located PEM. This suppression may be due to proximity of the macrophages to the developing tumor, macrophage maturational state, or both.

Alternative activation of tumor-associated macrophages by IL-4

“…59 Like IL-4-stimulated macrophages, TAMs also exhibit defective NO production, which in part accounts for their impaired tumoricidal activity. 60 Taken together, these data suggest IL-4 is likely involved in the attenuation of NO-dependent tumoricidal activity of TAMs by modulating the expression of arginine-catabolizing enzymes.…”

Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages

“…It is tempting to speculate that the impaired growth of tumors in Plg-deficient mice in this study is directly associated with the increased density of macrophages. Indeed, tumor-infiltrating macrophages are directly toxic to tumor cells through their production of reactive oxygen intermediates, NO, H 2 O 2 , and tumor necrosis factor-a, and indirectly toxic through the production tumor immunity-stimulating interleukins (Alleva et al, 1994;Dinapoli et al, 1996;Elgert et al, 1998;Kono et al, 1996;Ohmori et al, 1995). However, tumor-infiltrating macrophages are also endowed with potent tumor promoting properties.…”

Monocytes and Macrophages in Cancer: Development and Functions

“…In sites of chronic unresolved inflammation, macrophages initially triggered by a pathogen or tissue stress, recruit monocytes that develop into additional inflammatory macrophages, producing cytokines and chemokines propagating and amplifying the inflammatory cascade [66]. Activated macrophages, located in the sub-epithelial spaces, can contribute to genetic mutations in the adjacent epithelial cells through the production of DNA-damaging reactive nitrogen and oxygen species [69][70][71]. Yet, if DNA repair fails and these mutations accumulate and stabilize, neoplasia can develop and lead to the production of a new wave of TDFs, including M-CSF and CCL2, which will influence the recruitment of more monocytes/macrophages.…”