The Study On The Molecular Mechanism Of Liver X Receptor-mediated Downregulation Of BAFF Expression

Background:B cell activation factor belonging to the TNF family (BAFF) is amember of TNF family and an important inflammatory agent expressed byB lymphocytes. Overexpression of BAFF is closely related to theoccurrence and development of various diseases (such as leukemia,rheumatoid arthritis, etc.). Therefore, inhibition of BAFF expression and itsrelevant biological function are of great importance to preventing andcuring BAFF-related diseases. Liver X receptor (LXR) is a typical memberof nuclear receptor super-family. As a multiple transcriptional factor, LXRplays important roles in metabolism regulation and anti-carcinogenesis byregulating the expression of numerous target genes. Anti-inflammation hasrecently been reported as a novel function of LXR and the underlyingmechanism is waiting to be clarified. Especially, it is unclear whether LXRexerts its anti-inflammatory function via downregulating BAFF. Toilluminate this issue will be helpful to further clarify the anti-inflammatarymechanism of LXR, and even provide scientific ground for exploring new measures to prevent and cure inflammation by targeting BAFF.Objects:To investigate the influence of LXR on expression of BAFF andrelevant mechanism.Methods and results:Human B lymphoma cell lines Namalwa and Daudi cells were usedin the experiments. The cells were treated with LXR-specific agonistGW3965for24hours. Then RT-PCR and Real-time PCR analysis showedthat LXR could dramatically inhibit BAFF expression at transcriptionallevel. Moreover, Western blot analysis revealed that LXR couldsignificantly suppress BAFF expression at translational level. Luciferasereporter assay showed that LXR could repress the transcriptional activity ofBAFF promoter, which was associated with BAFF promoter region of-1082～-361. Electrophoretic mobility shift assay(EMSA) and chromatinimmunoprecipitation(ChIP) assay indicated that LXR reduced the bindingactivity of NF-κB transcriptional factor, suggesting that LXR may suppressBAFF expression via negatively interfering with NF-κB signaling. The invivo experiment demonstrated that gavaging mice with LXR-specificligand GW3965for one week decreased BAFF expression in spleen tissuesrevealed by RT-PCR and Western blot.Conclusion:LXR agonist could dose dependently inhibit the expression of BAFF mRNA and protein in B lymphocyte cell lines. A possible mechanism forthis inhibition might be the suppression of NF-κB signaling pathway. Theanimal study showed that LXR could in vivo downregulate BAFF in mice.