Impaired Bcl3 up-regulation leads to enhanced lipopolysaccharide-induced interleukin (IL)-23P19 gene expression in IL-10(-/-) mice.

Abstract

Genetic and biochemical analyses show that IL-23p19 plays a central role in mediating bacteria-induced colitis in interleukin-10-deficient (IL-10(-/-)) mice. The molecular mechanisms responsible for the dysregulated innate host response leading to enhanced IL-23 gene expression in IL-10(-/-) mice are poorly understood. In this study, we investigated the role of Bcl3 in controlling LPS-induced IL-23p19 gene expression in bone marrow-derived dendritic cells (BMDC) isolated from IL-10(-/-) mice. We report higher IL-23p19 mRNA accumulation and protein secretion in LPS-stimulated BMDC isolated from IL-10(-/-) compared with WT mice. Lipopolysaccharide (LPS)-induced B cell leukemia 3 (Bcl3) expression was strongly impaired (90% decrease) in IL-10(-/-) BMDC compared with WT BMDC. Chromatin immunoprecipitation demonstrated enhanced RelA binding to the IL-23p19 promoter in IL-10(-/-) compared with WT BMDC. Bcl3 overexpression decreased LPS-induced IL-23p19 gene expression in IL-10(-/-) BMDC, which correlated with enhanced NF-kappaB p50 binding and decreased RelA binding to the gene promoter. Conversely, Bcl3 knockdown enhanced LPS-induced IL-23p19 gene expression in WT BMDC. Moreover, LPS-induced IL-23p19 gene expression was significantly enhanced in Bcl3(-/-) BMDC compared with WT BMDC. In conclusion, enhanced LPS-induced IL-23p19 gene expression in IL-10(-/-) mice is due to impaired Bcl3 expression leading to diminished p50 and enhanced RelA recruitment to the IL-23p19 promoter.

• Authors: Marcus Mühlbauer, Paula M Chilton, Thomas C Mitchell, Christian Jobin
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 21 Pg. 14182-9 (May 23 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18375954 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• B-Cell Lymphoma 3 Protein
• Bcl3 protein, mouse
• Interleukin-23
• Lipopolysaccharides
• NF-kappa B
• Proto-Oncogene Proteins
• RNA, Messenger
• Toll-Like Receptors
• Transcription Factors
• Interleukin-10

Topics

• Animals
• B-Cell Lymphoma 3 Protein
• Cells, Cultured
• Interleukin-10 (deficiency, genetics, metabolism)
• Interleukin-23 (genetics, metabolism)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Knockout
• NF-kappa B (metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA, Messenger (genetics)
• Toll-Like Receptors (metabolism)
• Transcription Factors (genetics, metabolism)
• Up-Regulation (drug effects)