This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Menetrier-Caux, C. Articles by Blay, J. Y. Search for Related Content PubMed PubMed Citation Articles by Menetrier-Caux, C. Articles by Blay, J. Y.

IL-4 Prevents the Blockade of Dendritic Cell Differentiation Induced by Tumor Cells¹

Unité Cytokine et Cancer, Institut National de la Santé et de la Recherche Médicale U-453, Centre Léon Bérard, 69373 Lyon Cedex 08, France

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 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⁺CD32⁺CD86⁺HLA-DR⁺CD115^lowCD23^lowCD1a^-) 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.

This article has been cited by other articles:

				T. A. Stephens, E. Nikoopour, B. J. Rider, M. Leon-Ponte, T. A. Chau, S. Mikolajczak, P. Chaturvedi, E. Lee-Chan, R. A. Flavell, S. M. M. Haeryfar, et al. Dendritic Cell Differentiation Induced by a Self-Peptide Derived from Apolipoprotein E J. Immunol., November 15, 2008; 181(10): 6859 - 6871. [Abstract] [Full Text] [PDF]

				P. Cheng, C. A. Corzo, N. Luetteke, B. Yu, S. Nagaraj, M. M. Bui, M. Ortiz, W. Nacken, C. Sorg, T. Vogl, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein J. Exp. Med., September 29, 2008; 205(10): 2235 - 2249. [Abstract] [Full Text] [PDF]

				A. S. Lo, P. Gorak-Stolinska, V. Bachy, M. A. Ibrahim, D. M. Kemeny, and J. Maher Modulation of dendritic cell differentiation by colony-stimulating factor-1: role of phosphatidylinositol 3'-kinase and delayed caspase activation J. Leukoc. Biol., December 1, 2007; 82(6): 1446 - 1454. [Abstract] [Full Text] [PDF]

				L. Bracci, F. Moschella, P. Sestili, V. La Sorsa, M. Valentini, I. Canini, S. Baccarini, S. Maccari, C. Ramoni, F. Belardelli, et al. Cyclophosphamide Enhances the Antitumor Efficacy of Adoptively Transferred Immune Cells through the Induction of Cytokine Expression, B-Cell and T-Cell Homeostatic Proliferation, and Specific Tumor Infiltration Clin. Cancer Res., January 15, 2007; 13(2): 644 - 653. [Abstract] [Full Text] [PDF]

				A. E. M. Dirkx, M. G. A. oude Egbrink, J. Wagstaff, and A. W. Griffioen Monocyte/macrophage infiltration in tumors: modulators of angiogenesis J. Leukoc. Biol., December 1, 2006; 80(6): 1183 - 1196. [Abstract] [Full Text] [PDF]

				E. Gottfried, L. A. Kunz-Schughart, S. Ebner, W. Mueller-Klieser, S. Hoves, R. Andreesen, A. Mackensen, and M. Kreutz Tumor-derived lactic acid modulates dendritic cell activation and antigen expression Blood, March 1, 2006; 107(5): 2013 - 2021. [Abstract] [Full Text] [PDF]

				Y. Nefedova, S. Nagaraj, A. Rosenbauer, C. Muro-Cacho, S. M. Sebti, and D. I. Gabrilovich Regulation of Dendritic Cell Differentiation and Antitumor Immune Response in Cancer by Pharmacologic-Selective Inhibition of the Janus-Activated Kinase 2/Signal Transducers and Activators of Transcription 3 Pathway Cancer Res., October 15, 2005; 65(20): 9525 - 9535. [Abstract] [Full Text] [PDF]

				J. S. Ahn and B. Agrawal IL-4 is more effective than IL-13 for in vitro differentiation of dendritic cells from peripheral blood mononuclear cells Int. Immunol., October 1, 2005; 17(10): 1337 - 1346. [Abstract] [Full Text] [PDF]

				G. Li, Y.-J. Kim, and H. E. Broxmeyer Macrophage Colony-Stimulating Factor Drives Cord Blood Monocyte Differentiation into IL-10highIL-12absent Dendritic Cells with Tolerogenic Potential J. Immunol., April 15, 2005; 174(8): 4706 - 4717. [Abstract] [Full Text] [PDF]

				H. Okada, T. Tsugawa, H. Sato, N. Kuwashima, A. Gambotto, K. Okada, J. E. Dusak, W. K. Fellows-Mayle, G. D. Papworth, S. C. Watkins, et al. Delivery of Interferon-{alpha} Transfected Dendritic Cells into Central Nervous System Tumors Enhances the Antitumor Efficacy of Peripheral Peptide-Based Vaccines Cancer Res., August 15, 2004; 64(16): 5830 - 5838. [Abstract] [Full Text] [PDF]

				S. Negrier, D. Perol, C. Menetrier-Caux, B. Escudier, M. Pallardy, A. Ravaud, J.-Y. Douillard, C. Chevreau, C. Lasset, and J.-Y. Blay Interleukin-6, Interleukin-10, and Vascular Endothelial Growth Factor in Metastatic Renal Cell Carcinoma: Prognostic Value of Interleukin-6--From the Groupe Francais d'Immunotherapie J. Clin. Oncol., June 15, 2004; 22(12): 2371 - 2378. [Abstract] [Full Text] [PDF]

				P. Monti, B. E. Leone, A. Zerbi, G. Balzano, S. Cainarca, V. Sordi, M. Pontillo, A. Mercalli, V. Di Carlo, P. Allavena, et al. Tumor-Derived MUC1 Mucins Interact with Differentiating Monocytes and Induce IL-10highIL-12low Regulatory Dendritic Cell J. Immunol., June 15, 2004; 172(12): 7341 - 7349. [Abstract] [Full Text] [PDF]

				E. J. Ryan, A. J. Marshall, D. Magaletti, H. Floyd, K. E. Draves, N. E. Olson, and E. A. Clark Dendritic Cell-Associated Lectin-1: A Novel Dendritic Cell-Associated, C-Type Lectin-Like Molecule Enhances T Cell Secretion of IL-4 J. Immunol., November 15, 2002; 169(10): 5638 - 5648. [Abstract] [Full Text] [PDF]

				C. C. Sombroek, A. G. M. Stam, A. J. Masterson, S. M. Lougheed, M. J. A. G. Schakel, C. J. L. M. Meijer, H. M. Pinedo, A. J. M. van den Eertwegh, R. J. Scheper, and T. D. de Gruijl Prostanoids Play a Major Role in the Primary Tumor-Induced Inhibition of Dendritic Cell Differentiation J. Immunol., May 1, 2002; 168(9): 4333 - 4343. [Abstract] [Full Text] [PDF]