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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049383-08
Application #
7587385
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Minnicozzi, Michael
Project Start
2001-06-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
8
Fiscal Year
2009
Total Cost
$291,357
Indirect Cost
Name
University of Maryland College Park
Department
Anatomy/Cell Biology
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Fleming, Bryan D; Mosser, David M (2011) Regulatory macrophages: setting the threshold for therapy. Eur J Immunol 41:2498-502
Mosser, David M; Zhang, Xia (2011) Measuring opsonic phagocytosis via Fc? receptors and complement receptors on macrophages. Curr Protoc Immunol Chapter 14:Unit 14.27
Briken, Volker; Mosser, David M (2011) Editorial: switching on arginase in M2 macrophages. J Leukoc Biol 90:839-41
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
Halstead, Scott B; Mahalingam, Suresh; Marovich, Mary A et al. (2010) Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis 10:712-22
Reis, Maria Letícia Costa; Ferreira, Vanessa Martins; Zhang, Xia et al. (2010) Murine immune response induced by Leishmania major during the implantation of paraffin tablets. Virchows Arch 457:609-18
Gallo, Paul; Gonçalves, Ricardo; Mosser, David M (2010) The influence of IgG density and macrophage Fc (gamma) receptor cross-linking on phagocytosis and IL-10 production. Immunol Lett 133:70-7
Yang, Ziyan; Zhang, Xia; Darrah, Patricia A et al. (2010) The regulation of Th1 responses by the p38 MAPK. J Immunol 185:6205-13
Zhang, Xia; Edwards, Justin P; Mosser, David M (2009) The expression of exogenous genes in macrophages: obstacles and opportunities. Methods Mol Biol 531:123-43
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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