Open AccessDefective feedback regulation of NF-κB underlies Sjögren ’ s syndrome in mice with mutated κB enhancers of the IκBα promoter
Author(s) -
Bailu Peng,
Jianhua Ling,
Andrew Joon Lee,
Zilai Wang,
Zhe Chang,
Wei Jin,
Ya’an Kang,
Richard Zhang,
David Shim,
Huamin Wang,
Jason B. Fleming,
Hui Zheng,
Shao Cong Sun,
Paul J. Chiao
Publication year - 2010
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1005533107
Subject(s) - enhancer , nf κb , transcription factor , biology , transcription (linguistics) , mutant , microbiology and biotechnology , gene , signal transduction , genetics , linguistics , philosophy
Feedback regulation of transcription factor NF-κB by its inhibitor IκBα plays an essential role in control of NF-κB activity. To understand the biological significance of IκBα-mediated feedback regulation of NF-κB, we generated mice harboring mutated κB enhancers in the promoter of theIκBα gene (IκBαM/M ) to inhibit NF-κB–regulated IκBα expression. Here, we report that these mutant mice are defective in NF-κB–induced expression of IκBα. This defective feedback regulation of NF-κB by IκBα not only altered activity of NF-κB, but also the expression of NF-κB–regulated genes. As a result,IκBαM/M , the homozygous knock-in mice with mutated κB enhancers in theIκBα promoter, acquire shorten life span, hypersensitivity to septic shock, abnormal T-cell development and activation, and Sjögren’ s Syndrome. These findings therefore demonstrate that the IκBα-mediated feedback regulation of NF-κB has an essential role in controlling T-cell development and functions, provide mechanistic insight into the development of Sjögren’ s Syndrome, and suggest the potential of NF-κB signaling as a therapeutic target for Sjögren’ s Syndrome and other autoimmune diseases.