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Mononuclear Phagocyte-Derived IL-10 Suppresses the Innate IL-12/IFN- Axis in Lung-Challenged Aged Mice¹

Bo-Chin Chiu^2,*, Valerie R. Stolberg and Stephen W. Chensue^2,*,

^* Department of Cellular and Molecular Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and Department of Pathology and Laboratory Medicine, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI 48105

Previously, we reported that IL-10-producing mononuclear phagocytes increase in lungs of aged mice, causing impaired innate cytokine expression. Since dendritic cells (DCs) contribute to innate NK cell and adaptive T cell immunity, we tested the hypothesis that age-related IL-10 might influence DC function with effects on NK and T cell activation. The results showed that DC recruitment to sites of lung inflammation was normal in aged mice (>20 mo). However, IFN--producing NK cells in LPS-challenged lungs were decreased in aged as compared with young mice, which was associated with increased IL-10⁺CD11b⁺Gr-1^lowCD11c^– cells consistent with mononuclear phagocytes. In vivo or in vitro blockade of IL-10 signaling restored IFN--producing NK cells. This restoration was reversed by IL-12 neutralization, indicating that IL-10 suppressed sources of IL-12 in aged mice. To probe DC function in adaptive immunity, we transferred young naive OVA-specific TCR transgenic T cells to old mice. Following challenge with OVA plus LPS, Ag presentation in the context of MHC-I and MHC-II occurred with similar kinetics and intensity in draining lymph nodes of young and old recipients as measured by proliferation. Despite this, aged hosts displayed impaired induction of IFN-⁺CD4⁺, but not IFN-⁺CD8⁺, effector T cells. Blockade of IL-10 signaling reversed age-associated defects. These studies indicate that the innate IL-12/IFN- axis is not intrinsically defective in lungs of aged mice, but is rather suppressed by enhanced production of mononuclear phagocyte-derived IL-10. Our data identify a novel mechanism of age-associated immune deficiency.

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 the American Federation for Aging Research and the Department of Veterans Affairs.

² Address correspondence and reprint requests to Dr. Bo-Chin Chiu or Dr. Stephen W. Chensue, Department of Pathology, University of Michigan Medical School, M5231 Medical Science I, 1301 Catherine, Ann Arbor, MI 48109. E-mail addresses: bawbajq{at}umich.edu and schensue{at}umich.edu

³ Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern; DC, dendritic cell; MLN, mediastinal lymph node; MPS, mononuclear phagocyte system; PPD, purified protein derivative.