The innate response to pathogen-derived products has been well-described. In general terms, exposure of macrophages or dendritic cells to bacteria or bacterial products results in a predictable array of inflammatory cytokines, produced in response to a well-described series of signaling intermediates. This has not been the case with the production of IL-10. Although it is well-appreciated that IL-10 is a regulatory cytokine that can dampen the initial inflammatory response, the mechanism(s) of IL-10 gene regulation and the conditions under which IL-10 is produced are not well understood. In the present application we seek to understand how macrophages and dendritic cells make the decision to produce IL-10. In the previous support period we made the observation that stimulating macrophages in the presence of immune complexes could induce the production of high levels of IL-10. In this renewal we propose to use this model of IL-10 superinduction to understand how the IL-10 gene is regulated. We will examine the signal transduction pathways leading to IL-10 production. We present data indicating that activation of the MARK, ERK, is required for IL-10 production. ERK activation leads to histone H3 phosphorylation at the IL-10 promoter, making the promoter more accessible to transcription factors. We think these studies on the regulation of IL-10 are important because IL-10 can prevent the dysregulated overproduction of inflammatory cytokines, which can be deleterious to a host during autoimmune disease. Conversely, the overproduction of IL-10 can suppress an otherwise productive immune response and lead to susceptibility to infections. Thus, controlling IL-10 production may represent a key to regulating host immune/inflammatory responses.
The specific aims of this proposal are to study: 1. The molecular mechanisms that allow the MARK pathway to influence IL-10 production. 2. The role for NF-?B1 in IL-10 gene regulation. 3. The heterogeneity of activated macrophages. Our goal is to understand how IL-10 is regulated so we can develop molecules to enhance or inhibit its production.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
Program Officer
Dong, Gang
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University of Maryland College Park
Anatomy/Cell Biology
Schools of Earth Sciences/Natur
College Park
United States
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Goncalves, Ricardo; Zhang, Xia; Cohen, Heather et al. (2011) Platelet activation attracts a subpopulation of effector monocytes to sites of Leishmania major infection. J Exp Med 208:1253-65
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Edwards, Justin P; Zhang, Xia; Mosser, David M (2009) The expression of heparin-binding epidermal growth factor-like growth factor by regulatory macrophages. J Immunol 182:1929-39

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