Defective feedback regulation of NF-kappaB underlies Sjogren's syndrome in mice with mutated kappaB enhancers of the IkappaBalpha promoter.
Feedback regulation of transcription factor NF-kappaB by its inhibitor IkappaBalpha plays an essential role in control of NF-kappaB activity. To understand the biological significance of IkappaBalpha-mediated feedback regulation of NF-kappaB, we generated mice harboring mutated kappaB enhancers in the promoter of the IkappaBalpha gene (IkappaBalpha(M/M)) to inhibit NF-kappaB-regulated IkappaBalpha expression. Here, we report that these mutant mice are defective in NF-kappaB-induced expression of IkappaBalpha. This defective feedback regulation of NF-kappaB by IkappaBalpha not only altered activity of NF-kappaB, but also the expression of NF-kappaB-regulated genes. As a result, IkappaBalpha(M/M), the homozygous knock-in mice with mutated kappaB enhancers in the IkappaBalpha 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 IkappaBalpha-mediated feedback regulation of NF-kappaB 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-kappaB signaling as a therapeutic target for Sjögren's Syndrome and other autoimmune diseases.
Peng
Bailu
B
Departments of Surgical Oncology-Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Ling
Jianhua
J
Lee
Andrew Joon
AJ
Wang
Zilai
Z
Chang
Zhe
Z
Jin
Wei
W
Kang
Ya'an
Y
Zhang
Richard
R
Shim
David
D
Wang
Huamin
H
Fleming
Jason B
JB
Zheng
Hui
H
Sun
Shao-Cong
SC
Chiao
Paul J
PJ
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D025461:Feedback, Physiological; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D017931:DNA Primers; D020672:I-kappa B Proteins; D050505:Mutant Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha