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 #
5R01AI049383-07
Application #
7388273
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
2008-04-01
Budget End
2009-03-31
Support Year
7
Fiscal Year
2008
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
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
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
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

Showing the most recent 10 out of 27 publications