IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells

Malignant cells may escape from the immune response in vivo because of a de fective differentiation of professional antigen-presenting cells (APCs), Le ., dendritic cells (DCs). We recently reported that tumor cells release int erleukin (LC)-6 and macrophage colony stimulating factor (M-CSF), which inh ibit the differentiation of CD34(+) cells into DCs and promote their commit ment toward monocytic lineage with a poor APC function. The results present ed here show that both IL-4 and IL-13 reverse the inhibitory effects of ren al cell carcinoma conditioned media (RCC CM) or IL-6+M-CSF on the phenotypi c 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 productio n of M-CSF, thereby preventing the loss of granulocyte macrophage colony st imulating factor (GM-CSF) receptor Lu chain expression on differentiating C D34(+) cells. Consistent with these observations, the differentiation of DC s from monocytes cultured with GM-CSF and IL-4 was also impaired by RCC Chi , but the minimal inhibitory concentrations of RCC CM were 10-fold higher t han for CD34(+) cells. In these conditions, monocytes cultured with GM-CSF and IL-4 also exhibited profound phenotypic changes (CD14(+) CD32(+)CD86(+) HLA-DR(+)CD115(low)CD23(low)CD1a(-)) and a poor APC function. These alterat ions were overcome in a dose-dependent manner by IL-4 (5-500 IU/ml), althou gh not beyond a 40% final concentration of RCC CM. The capacity of RCC CM t o 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 diff erentiation.