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Exposure of Myeloid Dendritic Cells to Exogenous or Endogenous IL-10 during Maturation Determines Their Longevity¹

W. L. William Chang^2,*, Nicole Baumgarth^*, Meghan K. Eberhardt^*, C. Y. Daniel Lee^*, Colin A. Baron, Jeff P. Gregg and Peter A. Barry^*,

^* Center for Comparative Medicine and Department of Medical Pathology, University of California, Davis, CA 95616

Dendritic cells (DC) are essential for the initiation of primary adaptive immune responses, and their functionality is strongly down-modulated by IL-10. Both innate and adaptive immune signals trigger the up-regulation of antiapoptotic Bcl-2 family members to facilitate the survival of DCs after maturation. However, whether IL-10 alters the expression of apoptotic-related genes in maturing DCs has not been determined. In this study, we demonstrate that spontaneous apoptosis rapidly occurred in myeloid DCs exposed to exogenous IL-10 upon maturation. Microarray analysis indicates that IL-10 suppressed the induction of three antiapoptotic genes, bcl-2, bcl-x, and bfl-1, which was coincident with the increased sensitivity of mature DCs to spontaneous apoptosis. IL-10 markedly inhibited the accumulation of steady state Bcl-2 message and protein in myeloid DCs activated through TLRs or TNFR family members, whereas exogenous IL-10 affected Bcl-x_L expression in a moderate manner. In contrast, bcl-2 expression of plasmacytoid DCs was less sensitive to the effects of IL-10. We further show that autocrine IL-10 significantly limited the longevity of myeloid DCs and altered the expression kinetics of Bcl-2 but not Bcl-x_L in maturing DCs. We conclude that the degree of IL-10 exposure and/or the level of endogenous IL-10 production upon myeloid DC maturation play a critical role in determining DC longevity. This regulatory mechanism of IL-10 is associated with the dynamic control of antiapoptotic Bcl-2 proteins.

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 in part by National Institutes of Health Grants AI49342 (to P.A.B.) and AI055881 (to N.B.).

² Address correspondence and reprint requests to Dr. W. L. William Chang, Center for Comparative Medicine, University of California, Davis, County Road 98 and Hutchison Drive, Davis, CA 95616. E-mail address: wlchang{at}ucdavis.edu

³ Abbreviations used in this paper: DC, dendritic cell; PDC, plasmacytoid DC; hIL-10, human IL-10; MDDC, monocyte-derived DC; poly(I:C), polyinosinic-polycytidylic acid; sCD40L, soluble CD40L; PI, propidium iodide; FSC, forward scatter; SSC, side scatter; PAMP, pathogen-associated molecular pattern; MFI, mean fluorescence intensity; BH, Bcl-2 homology; LTA, lipoteichoic acid; cmvIL-10, human CMV-encoded IL-10.