The IkappaB protein Bcl-3 negatively regulates transcription of the IL-10 gene in macrophages.
NF-kappaB/Rel transcription factors, implicated in inflammatory and immune responses against pathogens, are regulated by IkappaB proteins. The physiological and molecular function of the IkappaB family member Bcl-3 is understood only poorly. In this study, the role of Bcl-3 in an innate immune response was examined by gene targeting. We demonstrate that Bcl-3(-/-) mice are highly susceptible to Listeria monocytogenes infection. This correlates with diminished production of IL-12 p70 and IFN-gamma in vivo, which is mainly due to elevated synthesis of IL-10. Isolated peritoneal macrophages from Bcl-3(-/-) mice also produce elevated amounts of IL-10, which inhibit IL-12 p70 synthesis in an autocrine fashion. Thus, these data establish Bcl-3 as an inhibitor of IL-10 expression in macrophages. Furthermore, we show that Bcl-3 is not implicated in IL-10 mRNA stabilization but regulates the initiation of IL-10 transcription. Taken together, our results show that an essential function of Bcl-3 during an innate immune response against bacteria is to inhibit transcription of the IL-10 gene in macrophages.
Riemann
Marc
M
Department of Internal Medicine II, Technical University of Munich, Munich, Germany.
Endres
Robert
R
Liptay
Susanne
S
Pfeffer
Klaus
K
Schmid
Roland M
RM
D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D015536:Down-Regulation; D020672:I-kappa B Proteins / Q000502:physiology; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics*; D018664:Interleukin-12 / Q000096:biosynthesis; D008088:Listeriosis / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D021122:Protein Subunits / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D020871:RNA Stability; D014157:Transcription Factors; D014158:Transcription, Genetic
D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D020672:I-kappa B Proteins; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma