title: IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells.
abstract: Malignant cells may escape from the immune response in vivo because of a defective differentiation of professional antigen-presenting cells (APCs), i.e., dendritic cells (DCs). We recently reported that tumor cells release interleukin (IL)-6 and macrophage colony stimulating factor (M-CSF), which inhibit the differentiation of CD34+ cells into DCs and promote their commitment toward monocytic lineage with a poor APC function. The results presented here show that both IL-4 and IL-13 reverse the inhibitory effects of renal cell carcinoma conditioned media (RCC CM) or IL-6+M-CSF on the phenotypic and functional differentiation of CD34+ into DCs. IL-4 was found to act through a rapid blockade of the expression of M-CSF and the IL-6 receptor-transducing chain (gp130), along with a decrease of the secondary production of M-CSF, thereby preventing the loss of granulocyte macrophage colony stimulating factor (GM-CSF) receptor alpha chain expression on differentiating CD34+ cells. Consistent with these observations, the differentiation of DCs from monocytes cultured with GM-CSF and IL-4 was also impaired by RCC CM, but the minimal inhibitory concentrations of RCC CM were 10-fold higher than for CD34+ cells. In these conditions, monocytes cultured with GM-CSF and IL-4 also exhibited profound phenotypic changes (CD14+ D32+ CD86+ HLA-DR+ CD115(low) CD23(low) CD1a-) and a poor APC function. These alterations were overcome in a dose-dependent manner by IL-4 (5-500 IU/ml), although not beyond a 40% final concentration of RCC CM. The capacity of RCC CM to block DC differentiation from monocytes strongly correlated with IL-6 and M-CSF concentrations in medium. Taken together, these results demonstrate that IL-4 and IL-13 reverse the inhibitory effect of tumor cells on DC differentiation.
authors: Unité Cytokine et Cancer, Institut National de la Santé et de la Recherche Médicale U-453, Centre León Bérard, Lyon, France.
authors: C
authors: C
authors: Menetrier-Caux
authors: M C
authors: MC
authors: Thomachot
authors: L
authors: L
authors: Alberti
authors: G
authors: G
authors: Montmain
authors: J Y
authors: JY
authors: Blay
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis; D018952:Antigens, CD34 / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003470:Culture Media; D050822:Cytokine Receptor gp130; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D003470:Culture Media; C494199:IL6ST protein, human; D018793:Interleukin-13; D008562:Membrane Glycoproteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D050822:Cytokine Receptor gp130; D015847:Interleukin-4; D016186:Receptor, Macrophage Colony-Stimulating Factor