Renal cell carcinoma induces interleukin 10 and prostaglandin E2 production by monocytes.
Immunotherapy with interleukin 2 (IL-2) is not an effective anti-cancer treatment in the majority of patients with renal cell carcinoma (RCC), suggesting that the activation of cytotoxic T cells or NK cells may be impaired in vivo in these patients. The production of immunosuppressive factors by RCC was investigated. Using immunohistochemistry, IL-10 was detectable in 10 of 21 tumour samples tested. IL-10 was undetectable in the supernatant of cell lines derived from these RCCs. However, these cell lines or their conditioned medium (RCC CM), but not normal renal epithelial cells adjacent to the RCC or breast carcinoma cell lines, were found to induce IL-10, as well as prostaglandin E2 (PGE2) and tumour necrosis factor (TNF)alpha production by autologous or allogeneic peripheral blood mononuclear cells (PBMCs) and monocytes. IL-10 production induced by RCC CM was found to be dependent on TNF-alpha and PGE2 since an anti-TNF-alpha antibody (Ab) inhibited 40-70% of IL-10 production by monocytes, and the combination of anti-TNF-alpha Ab and indomethacin, an inhibitor of PGE2 production, inhibited 80-94% of RCC CM-induced IL-10 production by monocytes. The RCC CM of the five cell lines tested were found to induce a down-regulation of the expression of HLA-DR and CD86, as well as a strong inhibition of mannose receptor-dependent endocytosis by monocytes. The blockade of HLA-DR and CD86 expression was partially abrogated by indomethacin and anti-IL-10 Ab respectively, and completely abrogated by an anti-TNF-alpha Ab. The inhibition of mannose receptor-dependent endocytosis was partially abrogated by an anti-IL-10 Ab and completely abrogated by an anti-TNF-alpha Ab. These results indicate that RCCs induce IL-10, PGE2 and TNF-alpha production by monocytes, which down-regulate the expression of cell-surface molecules involved in antigen presentation as well as their endocytic capacity.
Unité Cytokine et Cancer, Centre Léon Bérard, Lyon, France.
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Ménétrier-Caux
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Bain
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Favrot
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Duc
J Y
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Blay
D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D017077:Culture Media, Conditioned; D017931:DNA Primers; D015232:Dinoprostone / Q000096:biosynthesis* / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D007680:Kidney Neoplasms / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D017077:Culture Media, Conditioned; D017931:DNA Primers; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015232:Dinoprostone