IL-10-inducible Bcl-3 negatively regulates LPS- induced TNF-alpha production in macrophages.
Interleukin-10 (IL-10) plays an important role in prevention of chronic inflammation in vivo. However, the molecular mechanism by which IL-10 exerts its anti-inflammatory response is poorly understood. Here, we performed a microarray analysis and identified Bcl-3 as an IL-10-inducible gene in macrophages. Lentiviral vector-mediated expression of Bcl-3 inhibited lipopolysaccharide (LPS)- induced production of tumor necrosis factor alpha ( TNF-alpha), but not IL-6, in macrophages. In Bcl-3-transduced and IL-10-pretreated macrophages, LPS-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) p65 was not impaired. However, DNA binding by NF-kappaB p50/ p65 was profoundly inhibited. Nuclear localization of Bcl-3 was associated with inhibition of LPS- induced TNF-alpha production. Overexpression of Bcl-3 suppressed activation of the TNF-alpha promoter, but not the IL-6 promoter. Bcl-3 interacted with NF-kappaB p50 and was recruited to the TNF-alpha promoter, but not the IL-6 promoter, indicating that Bcl-3 facilitates p50- mediated inhibition of TNF-alpha expression. Furthermore, Bcl-3-deficient macrophages showed defective IL-10- mediated suppression of LPS induction of TNF-alpha, but not IL-6. These findings suggest that IL-10- induced Bcl-3 is required for suppression of TNF-alpha production in macrophages.[1]References
- IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages. Kuwata, H., Watanabe, Y., Miyoshi, H., Yamamoto, M., Kaisho, T., Takeda, K., Akira, S. Blood (2003) [Pubmed]
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