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Three Sgp loci act independently as well as synergistically to elevate the expression of specific endogenous retroviruses implicated in murine lupus.

ABSTRACT: Endogenous retroviruses are implicated in murine lupus nephritis. They provide a source of nephritogenic retroviral gp70-anti-gp70 immune complexes through the production of serum gp70 protein and anti-gp70 autoantibodies as a result of the activation of TLR7. The Sgp (serum gp70 production) loci identified in lupus-prone mice play distinct roles for the expression of different classes of endogenous retroviruses, as Sgp3 regulates the transcription of xenotropic, polytropic and modified polytropic (mPT) viruses, and Sgp4 the transcription of only xenotropic viruses. In the present study, we extended these analyses to a third locus, Sgp5, using BALB/c mice congenic for the NZW-derived Sgp5 allele and also explored the possible interaction of Sgp3 and Sgp4 loci to promote the expression of endogenous retroviruses and serum gp70. The analysis of Sgp5 BALB/c congenic mice demonstrated that the Sgp5 locus enhanced the expression of xenotropic and mPT viruses, thereby upregulating the production of serum gp70. These data indicate a distinct action of the Sgp5 locus on the expression of endogenous retroviruses, as compared with two other Sgp loci. Moreover, comparative analysis of C57BL/6 double congenic mice for Sgp3 and Sgp4 loci with single congenic mice revealed that Sgp3 and Sgp4 acted synergistically to elevate the transcription of the potentially replication-competent Xmv18 provirus and the production of serum gp70. This indicates that the combined effect of three different Sgp loci markedly enhance the expression of endogenous retroviruses and their gene product, serum gp70, thereby contributing to the formation of nephritogenic gp70-anti-gp70 immune complexes in murine lupus.

SUBMITTER: Ito K

PROVIDER: S-EPMC3672360 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Three Sgp loci act independently as well as synergistically to elevate the expression of specific endogenous retroviruses implicated in murine lupus.

Ito Kiyoaki K Baudino Lucie L Kihara Masao M Leroy Valérie V Vyse Timothy J TJ Evans Leonard H LH Izui Shozo S

Journal of autoimmunity 20130307

Endogenous retroviruses are implicated in murine lupus nephritis. They provide a source of nephritogenic retroviral gp70-anti-gp70 immune complexes through the production of serum gp70 protein and anti-gp70 autoantibodies as a result of the activation of TLR7. The Sgp (serum gp70 production) loci identified in lupus-prone mice play distinct roles for the expression of different classes of endogenous retroviruses, as Sgp3 regulates the transcription of xenotropic, polytropic and modified polytrop ...[more]

PMID: 23465716

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Project description:BACKGROUND:Systemic lupus erythematosus (SLE) is an autoimmune inflammatory rheumatic disease. SLE susceptibility is affected by multiple genetic elements, environmental factors, and their interactions. We aimed in this study to statistically and functionally characterize a gene-gene interaction (epistasis) recently documented to affect SLE risk. METHODS:Two single-nucleotide polymorphisms, rs2230926 in TNFAIP3 (A20) gene and rs131654 in UBE2L3 (UBCH7) gene, were genotyped in all 3525 Korean participants, and their SLE risk association and epistasis were statistically analyzed by calculating odds ratio (OR), 95% confidence interval (CI), and P values in genotype comparisons between 1318 SLE patients and 2207 healthy controls. Furthermore, their effects on gene functions were assessed by comparatively examining separate and combined effects of TNFAIP3 and UBE2L3 knockdowns on NF-?B transcription factor activity in human cells. RESULTS:SLE susceptibility is associated with TNFAIP3 rs2230926 (OR?=?1.9, 95% CI 1.6-2.4, P =?8.6?×?10-11) and UBE2L3 rs131654 (OR?=?1.2, 95% CI 1.1-1.4, P =?1.1?×?10-4) in a Korean population of this study. Their risk-associated alleles synergistically elevate SLE susceptibility in both multivariate logistic regression analysis (ORinteraction =?1.6, P =?0.0028) and genotype-stratified analysis (ORinteraction =?2.4), confirming the synergistic TNFAIP3-UBE2L3 interaction in SLE risk. Additionally, the SLE-susceptible alleles confer decreased TNFAIP3 expression (P =?1.1?×?10-6, n =?610) and increased UBE2L3 expression (P =?9.5?×?10-11, n =?475), respectively, in B cell analysis of the International HapMap Project individuals with adjustment for ethnicity. Furthermore, when compared with TNFAIP3 non-knockdown and UBE2L3 knockdown in human HeLa cells, TNFAIP3 knockdown and UBE2L3 non-knockdown synergistically increase three cytokines, CCL2, CXCL8 (IL8), and IL6, all regulated by NF-?B in the human TNFR signaling pathway. CONCLUSIONS:A synergistic interaction between TNFAIP3 and UBE2L3 genes is observed in SLE risk, as being evident in comparison of genotype distributions between SLE patients and controls. Additionally, the synergistic gene-gene interaction is functionally validated, as TNFAIP3 reduction and UBE2L3 augment exert synergism in activation of NF-?B and subsequent induction of inflammatory cytokines. Accordingly, SLE inflammation and risk could be synergistically alleviated by TNFAIP3 upregulation and UBE2L3 downregulation.

Dataset Information

Three Sgp loci act independently as well as synergistically to elevate the expression of specific endogenous retroviruses implicated in murine lupus.

Publications

Three Sgp loci act independently as well as synergistically to elevate the expression of specific endogenous retroviruses implicated in murine lupus.

Similar Datasets

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