Ifi202, an IFN-inducible candidate gene for lupus susceptibility in NZB/W F1 mice, is a positive regulator for NF-kappaB activation in dendritic cells.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies and lupus nephritis. The [New Zealand black (NZB) x New Zealand white (NZW)]F1 (BWF1) mouse has been recognized as an important animal model of human SLE. The T(h)1-prone phenotype of BWF1 mice has been shown to contribute to the development of the lupus. However, the molecular basis for T(h)1 skewing in BWF1 mice has not been clarified. We noticed that IL-6, IL-12 and other proinflammatory cytokines as well as IkappaB-zeta induction were higher in mature bone marrow-derived dendritic cells (BMDCs) from NZB and BWF1 mice than those from NZW mice. The expression of an IFN-inducible gene Ifi202, a candidate gene for lupus, was almost undetectable in NZW BMDCs. Thus, we hypothesized that Ifi202 is involved in elevated IL-12 production from BWF1 BMDCs. Overexpression of Ifi202 enhanced the LPS-induced IkappaB-zeta, IL-12p40 and NF-kappaB promoter activities, while anti-sense (AS) RNA against Ifi202 strongly suppressed them in a monocytic cell line, RAW 264.7. Furthermore, overexpression of Ifi202 enhanced LPS-induced IL-12p40 and IkappaB-zeta mRNA induction while Ifi202 AS RNA suppressed these in RAW 264.7 cells. In addition, forced expression of Ifi202 enhanced IL-12p40 mRNA induction in NZW BMDCs. Thus, Ifi202 is an important NF-kappaB activator in DCs and involved in IL-12 production, which may account for a T(h)1-prone phenotype of BWF1 mice.
Yamauchi
Moriyasu
M
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Hashimoto
Masayuki
M
Ichiyama
Kenji
K
Yoshida
Ryoko
R
Hanada
Toshikatsu
T
Muta
Tatsushi
T
Komune
Shizuo
S
Kobayashi
Takashi
T
Yoshimura
Akihiko
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D007372:Interferons / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C092537:Ifi202b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D007372:Interferons