title: Defective feedback regulation of NF-kappaB underlies Sjogren's syndrome in mice with mutated kappaB enhancers of the IkappaBalpha promoter.
abstract: 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.
authors.affiliation: Departments of Surgical Oncology-Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Bailu
authors.initials: B
authors.lastname: Peng
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ling
authors.forename: Andrew Joon
authors.initials: AJ
authors.lastname: Lee
authors.forename: Zilai
authors.initials: Z
authors.lastname: Wang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chang
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Ya'an
authors.initials: Y
authors.lastname: Kang
authors.forename: Richard
authors.initials: R
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Shim
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
mesh_terms: 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
chemical_list: 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