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Interaction of mammalian cells with polymorphonuclear leukocytes: relative sensitivity to monolayer disruption and
I Ginsburg1, D F Gibbs, J Varani
1Department of Oral Biology, Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel.
Abstract:
Monolayers of murine fibrosarcoma cells that had been treated either with histone-opsonized streptococci, histone-opsonized Candida globerata, or lipoteichoic acid-anti-lipoteichoic acid complexes underwent disruption when incubated with human polymorphonuclear leukocytes (PMNs). Although the architecture of the monolayers was destroyed, the target cells were not killed. The destruction of the monolayers was totally inhibited by proteinase inhibitors, suggesting that the detachment of the cells from the monolayers and aggregation in suspension were induced by proteinases releases from the activated PMNs. Monolayers of normal endothelial cells and fibroblasts were much resistant to the monolayer-disrupting effects of the PMNs than were the fibrosarcoma cells. Although the fibrosarcoma cells were resistant to killing by PMNs, killing was promoted by the addition of sodium azide (a catalase inhibitor). This suggests that the failure of the PMNs to kill the target cells was due to catalase inhibition of the hydrogen peroxide produced by the activated PMNs. Target cell killing that occurred in the presence of sodium azide was reduced by the addition of a "cocktail" containing methionine, histidine, and deferoxamine mesylate, suggesting that hydroxyl radicals but not myeloperoxidase-catalyzed products were responsible for cell killing. The relative ease with which the murine fibrosarcoma cells can be released from their substratum by the action of PMNs, coupled with their insensitivity to PMN-mediated killing, may explain why the presence of large numbers of PMNs at the site of tumors produced in experimental animals by the fibrosarcoma cells is associated with an unfavorable outcome.
Insights
Murine fibrosarcoma cells are disrupted by human polymorphonuclear leukocytes (PMNs) but not killed, indicating PMN-derived proteinases cause detachment. This resistance to PMN killing may explain poor outcomes in fibrosarcoma tumor models.
Area of Science:
- Immunology
- Cell Biology
- Oncology
Background:
- Polymorphonuclear leukocytes (PMNs) are key immune cells involved in host defense.
- Tumor microenvironments often contain significant numbers of PMNs, with variable effects on tumor progression.
- The interaction between PMNs and cancer cells, particularly fibrosarcoma, requires further elucidation.
Purpose of the Study:
- To investigate the mechanisms by which PMNs interact with and affect murine fibrosarcoma cells.
- To determine if PMNs can kill fibrosarcoma cells and the factors influencing this interaction.
- To understand the implications of PMN-fibrosarcoma cell interactions in tumor progression.
Main Methods:
- Incubation of murine fibrosarcoma cell monolayers with activated human PMNs.
- Treatment of cells with opsonized bacteria, Candida, lipoteichoic acid complexes, proteinase inhibitors, sodium azide, and radical scavengers.
- Assessment of cell monolayer disruption, cell detachment, aggregation, and cell viability.
Main Results:
- PMNs disrupted fibrosarcoma cell monolayers, causing detachment and aggregation, mediated by PMN-derived proteinases.
- Fibrosarcoma cells were resistant to PMN-mediated killing, which was partially overcome by catalase inhibition (sodium azide).
- Hydroxyl radicals, not myeloperoxidase products, were identified as the primary cytotoxic agents in PMN-mediated killing.
Conclusions:
- PMN-induced disruption of fibrosarcoma monolayers is mediated by released proteinases.
- Fibrosarcoma cells evade PMN-mediated killing through mechanisms involving catalase and resistance to reactive oxygen species.
- The ability of fibrosarcoma cells to resist PMN-mediated killing and undergo PMN-induced detachment may contribute to unfavorable tumor outcomes.