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IL-10 Induces IL-10 in Primary Human Monocyte-Derived Macrophages via the Transcription Factor Stat3¹

Karl J. Staples^*, Timothy Smallie, Lynn M. Williams, Andy Foey^2,, Bernie Burke^*, Brian M. J. Foxwell and Loems Ziegler-Heitbrock^3,*,

^* Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, U.K.; Kennedy Institute of Rheumatology, Imperial College School of Medicine, London, U.K.; and Clinical Cooperation Group Inflammatory Lung Diseases, Asklepios Fachkliniken and GSF National Research Center, Robert Koch Allee 29, Gauting, Germany

IL-10 is an important immunosuppressive cytokine that can down-regulate expression of other cytokines and has been shown to down-regulate itself. We show, in this study, that treatment of human monocyte-derived macrophages with IL-10 induces IL-10 mRNA in a dose- and time-dependent manner with an optimum induction at 100 ng/ml and at 6 h, whereas IL-10-induced IL-10 protein can be detected at 18 h. In the same cells, IL-10 can partially suppress IL-10 mRNA induced by LPS, but only down to the level of IL-10-induced IL-10. An adenoviral luciferase reporter construct driven by the –195 IL-10 promoter, which contains a Stat motif, was readily induced by both IL-10 and LPS. Mutation of this Stat motif ablated IL-10 activation of this promoter, but not the LPS activation. Finally, we show that overexpression of a dominant-negative Stat3 protein will prevent IL-10 induction, but not LPS induction, of IL-10 mRNA. These data show that IL-10 induces IL-10 in monocyte-derived macrophages in an autocrine manner via activation of the transcription factor Stat3.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant 91-C19230 from the Biotechnology and Biological Sciences Research Council.

² Current address: School of Biological Sciences, University of Plymouth, Drake Circus, Plymouth, U.K.

³ Address correspondence and reprint requests to Dr. Loems Ziegler-Heitbrock, Department of Infection, Immunity and Inflammation, University of Leicester, Medical Sciences Building, University Road, Leicester, U.K. E-mail address: lzh1{at}leicester.ac.uk

⁴ Abbreviations used in this paper: MDM, monocyte-derived macrophage; rhIL-10, recombinant human IL-10; AdV, adenovirus; MOI, multiplicity of infection; PMB, polymyxin B; S.ae, Salmonella abortus equii; WT, wild type; IRF, IFN regulatory factor; dn, dominant negative; ₂m, ₂-microglobulin; m, murine; h, human.

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