: Bacterial products invoke profuse cytokine production from mammalian leukocytes. Most of these cytokines are proinflammatory in nature and play an integral role in the innate immune response to pathogens. These cytokines include TNFalpha, IL-1,IL-6 and IL-12. In addition to these proinflammatory cytokines, leukocytes also typically produce modest amounts of antiinflammatory cytokines with the potential to dampen innate inflammatory responses. These antiinflammatory cytokines include IL-10 and TGFbeta. The regulation of cytokine production is important because the excess production of proinflammatory cytokines has been associated with endotoxic shock and with a variety of autoimmune pathologies. In the present proposal we will examine a novel way to manipulate macrophages to preferentially make antiinflammatory cytokines in response to bacterial products. We have previously demonstrated that the ligation of phagocytic receptors on macrophages can modulate cytokine production. In the present proposal we will focus our studies on the macrophage Fc-gamma receptors because they are particularly adept at influencing cytokine production. The ligation of specific macrophage Fc-gammaR efficiently turns off IL-12 transcription and induces the production of high amounts of IL-10. The IL-10 that is produced by these macrophages is biologically active and can dramatically alter macrophage physiology. Thus, the macrophage Fc-gammaRs can alter the fundamental nature of the innate response to bacterial products. In the present proposal we plan to explore the molecular nature of these alterations in cytokine production with an eye to the development of novel classes of antiinflammatory compounds that modulate macrophage cytokine responses. Specifically we will examine the molecular regulation of the transcription of IL-10 and IL-12. The nature of the signaling responses through the Fc-gammaRs and specifically the role of the common gamma chain in signaling for IL-10 upregulation will be determined. Finally, in vivo models will be developed to determine the extent to which inflammatory responses can be blunted by Fc-gammaR ligation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049383-04
Application #
6747349
Study Section
Special Emphasis Panel (ZRG1-BM-1 (02))
Program Officer
Bocek, Petr
Project Start
2001-06-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$333,000
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
Yang, Ziyan; Zhang, Xia; Darrah, Patricia A et al. (2010) The regulation of Th1 responses by the p38 MAPK. J Immunol 185:6205-13
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
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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