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Recruitment of STAT3 for Production of IL-10 by Colon Carcinoma Cells Induced by Macrophage-Derived IL-6¹

Jean-Philippe Herbeuval^2,*, Eric Lelievre, Claude Lambert^*, Michel Dy and Christian Genin^*

^* Groupe Immunité des Muqueuses et Agents Pathogènes, University of Saint Etienne, Saint Etienne, France; Institut National de la Santé et de la Recherche Médicale Unité 564, Angers, France; and Centre National de la Recherche Scientifique Unité Mixte de Recherche 8603, Paris, France

The immunosuppressive cytokine IL-10 is associated with poor prognosis in colon cancer. Although macrophages are involved in antitumor defenses, production of IL-10 by tumor cells may permit malignant cells escape to cell-mediated immune defenses. To investigate interactions between macrophages and tumor cells in humans, we cultured macrophages isolated from patients and tested the effect of these macrophages on the production of IL-10 by several tumor cell lines. Macrophages were isolated from pleural effusions of patients with malignancy and from noncancer control patients. We demonstrated that culture supernatants of macrophages from both sources strongly stimulated IL-10 production by the three different human colon adenocarcinoma cell lines, Colo 205, Colo 320, and HT29. Recombinant IL-6, but not IL-10, TNF-, and IFN-, stimulated the secretion of IL-10 by colon tumor cells. mAbs against IL-6 and IL-6R prevented the effect of macrophage culture supernatants and of rIL-6, respectively, on the production of IL-10 by the three cell lines. Cocultures of macrophages and colon cancer cells showed that these tumor cells first stimulated macrophages to produce IL-6, which was then followed by IL-6-induced IL-10 production by colon cancer cells. Finally, we showed that IL-10 gene regulation was mediated by STAT3, which was phosphorylated after the binding of IL-6 to IL-6R. This is the first demonstration that IL-6, secreted by macrophages, can induce a STAT3-mediated IL-10 production by colon tumor cells.

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