Rheumatology Advance Access originally published online on May 30, 2003
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Rheumatology 2003; 42: 1155-1163
© 2003 British Society for Rheumatology
Protein interaction for an interferon-inducible systemic lupus associated gene, IFIT1
1Shanghai Clinical Centre of Rheumatic Diseases and Institute of Rheumatology, Department of Rheumatology, Renji Hospital, Shanghai Second Medical University, Shanghai, 2Structural Biology Laboratory, Division of Biology, Tsinghua University, Beijing, China, 3Division of Rheumatology, Department of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA and 4Health Science Centre, Institute for Biological Sciences, Chinese Academy of Sciences and Shanghai Second Medical University, Shanghai, China.
Correspondence to:
N. Shen, Department of Rheumatology, Renji Hospital, 145, Shandong Mid. Road, 200001, Shanghai, China. E-mail: shennand{at}online.sh.cn
Objective. To identify disease-related genes and immune-regulatory pathways in the pathogenesis of systemic lupus erythematosus (SLE) by using gene expression profiling and protein–protein interaction analysis.
Methods. Peripheral white blood cell gene expression profiles of 10 SLE patients were determined by oligonucleotide microarray analysis. Clustering of the gene expression profile was compared with the clinical immune phenotype. SLE-induced genes that were over- or under-expressed were determined and independently validated using a real-time polymerase chain reaction (PCR) method. To study their potential function and the possible pathways involved, a candidate gene was cloned and a GST (glutathione S-transferase) fusion protein was expressed in Escherichia coli. The fusion protein was further purified using the glutathione Sepharose 4B system, and was treated as bait to capture prey from SLE peripheral white blood cell lysate. MALDI-TOF (matrix-assisted laser desorption/ionization–time-of-flight) mass spectrometry was then performed to determine the prey protein.
Results. Similarity was found between the gene expression profile and the immune phenotype clusters of the SLE patients. More than 20 disease-associated genes were identified, some of which have not been related to SLE previously. Of these genes, a cluster of interferon-induced genes were highly correlated. IFIT1 (interferon-induced with tetratricopeptide repeats 1) was one of these genes, and overexpression of its mRNA was confirmed independently by real-time PCR in a larger population (40 SLE patients and 29 normal controls). An IFIT1 protein– protein interaction study showed that IFIT1 may interact with Rho/Rac guanine nucleotide exchange factor.
Conclusion. The gene expression profile seems to be the molecular basis of the diverse immune phenotype of SLE. On the basis of the SLE-related genes found in this study, we suggest that the interferon-related immune pathway is important in the pathogenesis of SLE. IFIT1 is the first gene described as a candidate gene for SLE, and may function by activating Rho proteins through interaction with Rho/Rac guanine nucleotide exchange factor. IFIT1 and the interferon-related pathway may provide potential targets for novel interventions in the treatment of SLE.
KEY WORDS: Systemic lupus erythematosus, Gene expression profile, Interferon, Interferon-induced protein with tetratricopeptide repeats 1, Protein–protein interaction.
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