Overexpression of interferon-activated gene 202 (Ifi202) correlates with the progression of autoimmune glomerulonephritis associated with the MRL chromosome 1.

Abstract

B6.MRLc1(82-100) congenic mice carrying the telomeric region of lupus-prone MRL chromosome 1 develop autoimmune glomerulonephritis (GN). The GN susceptibility locus of B6.MRLc1(82-100) contains the interferon activated gene 200 (Ifi200) family, which consists of Ifi202, 203, 204, and 205. Recently, Ifi202 was suggested as a candidate gene for murine lupus. In this study, we assessed the association between Ifi200 family and GN in several disease models. We compared the expression of Ifi200 family members in 24 organs between the C57BL/6 and B6.MRLc1(82-100). The expressions of Ifi200 family members differed between strains, and the most dramatic differences appeared in Ifi202 expression. Briefly, in the blood, immune organs, lungs, and testes mRNA expression was higher in B6.MRLc1(82-100) mice. In the kidney and immune organs, only Ifi202 expression increased with the development of GN in B6.MRLc1(82-100), and significant differences from C57BL/6 were observed even before disease onset. Ifi202 expression in the kidneys of BXSB, NZB/WF1, and MRL/lpr was also significantly high in the early- and late-disease stages. Furthermore, laser microdissection-reverse-transcriptase-polymerase chain reaction analysis confirmed the high Ifi202 expression in all areas of B6.MRLc1(82-100) kidneys. In conclusion, in the Ifi200 family, Ifi202 expressions in the kidney and immune organs significantly increased with GN progression.

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Title
Overexpression of interferon-activated gene 202 (Ifi202)
correlates with the progression of autoimmune
glomerulonephritis associated with the MRL chromosome 1
Author(s)
Ichii, Osamu; Kamikawa, Akihiro; Otsuka, Saori; Hashimoto,
Yoshiharu; Sasaki, Nobuya; Endoh, Daiji; Kon, Yasuhiro
CitationLupus, 19(8): 897-905
Issue Date2010-07
Doc URLhttp://hdl.handle.net/2115/46758
Right
The final, definitive version of this article has been published
in the Journal, Lupus, 19(8), 2010 of publication, © SAGE
Publications Ltd, 2010 by SAGE Publications Ltd at the Lupus
page: http://lup.sagepub.com/ on SAGE Journals Online:
http://online.sagepub.com/
Type article (author version)
Additional
Information
Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP

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TitleTitle: Overexpression of interferon-activated gene 202 (Ifi202) correlates with the
progression of autoimmune glomerulonephritis associated with the MRL
chromosome 1
AuthorsAuthors: Osamu ICHII1), Akihiro KAMIKAWA2), Saori OTSUKA1),3), Yoshiharu
HASHIMOTO1), 3), Nobuya SASAKI4), Daiji ENDOH5), and Yasuhiro KON1)
AffiliationsAffiliations: 1)Laboratory of Anatomy, Department of Biomedical Sciences, Graduate
School of Veterinary Medicine, Hokkaido University
2)Laboratory of Biochemistry, Department of Biomedical Sciences, Graduate School
of Veterinary Medicine, Hokkaido University
3)Office for Faculty Development and Teaching Enriched Veterinary Medicine,
Graduate School of Veterinary Medicine, Hokkaido University
4)Laboratory of Laboratory Animal Science and Medicine, Department of Disease
Control, Graduate School of Veterinary Medicine Hokkaido University
5)Department of Veterinary Radiology, School of Veterinary Medicine, Rakuno
Gakuen University
Corresponding authorCorresponding author: Yasuhiro Kon, DVM, PhD
Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of
Veterinary Medicine, Hokkaido University, Kita 18-Nishi 9, Kita-ku, Sapporo
060-0818, Japan
Tel & Fax: 011-706-5189
E-mail: y-kon@vetmed.hokudai.ac.jp
Running headRunning head: Ifi202 in murine autoimmune glomerulonephritis

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SummarySummary
B6.MRLc1(82-100) congenic mice carrying the telomeric region of lupus-prone
MRL chromosome 1 develop autoimmune glomerulonephritis (GN). The GN
susceptibility locus of B6.MRLc1(82-100) contains the Interferon activated gene 200
(Ifi200) family, which consists of Ifi202, 203, 204, and 205. Recently, Ifi202 was
suggested as a candidate gene for murine lupus. In this study, we assessed the
association between Ifi200 family and GN in several disease models. We compared
the expression of Ifi200 family members in 24 organs between the C57BL/6 and
B6.MRLc1(82-100). The expressions of Ifi200 family members differed between
strains, especially, the most dramatic differences appeared in Ifi202 expression.
Briefly, in the blood, immune organs, lungs, and testes was higher in
B6.MRLc1(82-100) mice. In the kidney and immune organs, only Ifi202 expression
increased with the development of GN in B6.MRLc1(82-100), and significant
differences from the C57BL/6 were observed even before disease onset. Ifi202
expression in the kidneys of BXSB, NZB/WF1, and MRL/lpr was also significantly
high in the early- and late-disease stages. Furthermore, laser
microdissection-RT-PCR analysis confirmed the high Ifi202 expression in all areas
of B6.MRLc1(82-100) kidneys. In conclusion, among Ifi200 family, Ifi202
expressions in the kidney and immune organs significantly increased with GN
progression.

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I Introductionntroduction
Interferons (IFNs), including types I (IFN-α and IFN-β) and II (IFN-γ), are a
family of cytokines, which play an important role in antiviral and natural
immunity.1 Binding of an IFN to its receptor induces the transcriptional activation
of IFN-stimulated genes via the activation of the Janus kinase-signal transducer
and activator of transcription (JAK-STAT) pathway.1, 2 The IFN activated gene 200
(Ifi200) family, including Ifi202, Ifi203, Ifi204, and Ifi205, consists of genes induced
by IFNs and are localized on the murine telomeric region of Chromosome 1 (Chr.1)
(95 cM).3 These genes encode highly homologous proteins and are suggested to play
an important role in the regulation of cellular growth, differentiation, survival, and
death in vitro.3 In humans, IFI16, MNDA, AIM2, and IFIX, which have high
homology with the murine Ifi200 family, are also localized on Chr.1q21–23.3, 4
Glomerulonephritis (GN) is caused by certain infections, tumors, drugs, and
autoimmune diseases. Systemic lupus erythematosus (SLE) is a polygenic
autoimmune disease characterized by multiorgan inflammation and the production
of autoantibodies. These autoantibodies form immune complexes and cause
autoimmune GN called lupus nephritis, which is a major cause of morbidity and
mortality both in humans with SLE and animal models of lupus.5 Some reports
suggest that SLE patients have increased serum IFN-α levels and their peripheral
blood cells show increased IFN-α expression, which indicate the activation of IFN-α
signaling.4, 6, 7 In addition, it has been suggested that increased IFN-inducible gene
expression is associated with the pathophysiology of lupus nephritic patients.8
BXSB, NZB/WF1, and MRL mice are important animal models of autoimmune
diseases.9 Bxs3 (71-99 cM) and Nba2 (92-94 cM) in the telomeric region of murine

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Chr.1 were reported as lupus susceptibility loci in BXSB and NZB-derived genomes,
respectively.9 Recently, Ifi202 in the Bxs3 and Nba2 loci was identified as a major
susceptibility gene by microarray analysis.10, 11 Furthermore, we discovered the
GN-susceptibility locus, named MRL autoimmune glomerulonephritis (Mag), which
is localized in the telomeric region of MRL Chr.1, by generating B6.MRLc1(82-100)
congenic mice having the telomeric region of MRL-type Chr.1 (82-100 cM) and the
C57BL/6 background.12 Aged B6.MRLc1(82-100) mice, especially females, exhibit
glomerular proliferative and membranous lesions with splenomegaly and serum
autoantibody levels.13, 14
The Ifi200 family is located in the Mag locus.12-14 In the present study, we
determined whether the expression of Ifi200 family members changed with the
development of GN in the B6.MRLc1(82-100) strain as well as several other murine
lupus models. We found that of all the Ifi200 family members, the overexpression of
only Ifi202 correlated with the onset of GN in the Ifi200 family.