Lingling Wu1, Yuting Qin1, Shiwei Xia1, Min Dai1, Xiao Han2, Yanfang Wu1, Xiaoyan Zhang1, Jianyang Ma1, Yan Wang2, Yuanjia Tang1, Zheng Liu3, Wei Zhu3, Bahija Jallal3, Yihong Yao4, Bo Qu1, Nan Shen5. 1. Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Shanghai Jiao Tong University School of Medicine, and Chinese Academy of Sciences, Shanghai, China. 3. MedImmune, Gaithersburg, Maryland. 4. Yihong Yao, PhD: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and MedImmune, Gaithersburg, Maryland. 5. Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Shanghai Jiao Tong University School of Medicine and Chinese Academy of Sciences, Shanghai, China; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Collaborative Innovation Center for Translational Medicine at Shanghai Jiao Tong University School of Medicine; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract
OBJECTIVE: Type I interferon (IFN) signaling is regarded as a central pathogenic pathway in systemic lupus erythematosus (SLE). Specific inhibition of this pathway is a core area for the development of new therapies for SLE. This study was undertaken to clarify the pathogenic mechanism involved and to identify new therapeutic targets, using a high-throughput screening platform to determine novel regulators that contribute to the overactivation of the type I IFN signaling pathway in SLE. METHODS: A high-throughput IFN-stimulated response element (ISRE)-luciferase assay was used to screen for candidate genes that regulate the IFN signaling pathway. Western blotting was used to confirm the regulatory function of CDK1. SYBR Green quantitative reverse transcriptase-polymerase chain reaction was used to detect the expression of individual IFN-stimulated genes (ISGs). The differential expression of CDK1 and ISGs in SLE patients and healthy controls was analyzed using RNA sequencing data and a microarray. RESULTS: The high-throughput ISRE-luciferase assay revealed that CDK1 enhanced type I IFN signaling. Consistent with this finding, CDK1 promoted the type I IFN-induced phosphorylation of STAT-1 and the up-regulated expression of ISGs. CDK1 expression was elevated in peripheral blood mononuclear cells (PBMCs) and kidney biopsy specimens from SLE patients and correlated positively with their IFN scores. A CDK1 inhibitor reduced the expression of ISGs in PBMCs from SLE patients and in renal cells from mice with lupus. CONCLUSION: Our findings indicate that CDK1 is a positive regulator of the IFN signaling pathway. The overexpression of CDK1 might contribute to the abnormally amplified type I IFN signaling in SLE, and the inhibition of CDK1 could be used to down-regulate type I IFN signaling in SLE.
OBJECTIVE:Type I interferon (IFN) signaling is regarded as a central pathogenic pathway in systemic lupus erythematosus (SLE). Specific inhibition of this pathway is a core area for the development of new therapies for SLE. This study was undertaken to clarify the pathogenic mechanism involved and to identify new therapeutic targets, using a high-throughput screening platform to determine novel regulators that contribute to the overactivation of the type I IFN signaling pathway in SLE. METHODS: A high-throughput IFN-stimulated response element (ISRE)-luciferase assay was used to screen for candidate genes that regulate the IFN signaling pathway. Western blotting was used to confirm the regulatory function of CDK1. SYBR Green quantitative reverse transcriptase-polymerase chain reaction was used to detect the expression of individual IFN-stimulated genes (ISGs). The differential expression of CDK1 and ISGs in SLEpatients and healthy controls was analyzed using RNA sequencing data and a microarray. RESULTS: The high-throughput ISRE-luciferase assay revealed that CDK1 enhanced type I IFN signaling. Consistent with this finding, CDK1 promoted the type I IFN-induced phosphorylation of STAT-1 and the up-regulated expression of ISGs. CDK1 expression was elevated in peripheral blood mononuclear cells (PBMCs) and kidney biopsy specimens from SLEpatients and correlated positively with their IFN scores. A CDK1 inhibitor reduced the expression of ISGs in PBMCs from SLEpatients and in renal cells from mice with lupus. CONCLUSION: Our findings indicate that CDK1 is a positive regulator of the IFN signaling pathway. The overexpression of CDK1 might contribute to the abnormally amplified type I IFN signaling in SLE, and the inhibition of CDK1 could be used to down-regulate type I IFN signaling in SLE.
Authors: Jonas Carlsson Almlöf; Andrei Alexsson; Juliana Imgenberg-Kreuz; Lina Sylwan; Christofer Bäcklin; Dag Leonard; Gunnel Nordmark; Karolina Tandre; Maija-Leena Eloranta; Leonid Padyukov; Christine Bengtsson; Andreas Jönsen; Solbritt Rantapää Dahlqvist; Christopher Sjöwall; Anders A Bengtsson; Iva Gunnarsson; Elisabet Svenungsson; Lars Rönnblom; Johanna K Sandling; Ann-Christine Syvänen Journal: Sci Rep Date: 2017-07-24 Impact factor: 4.379