Sle1ab mediates the aberrant activation of STAT3 and Ras-ERK signaling pathways in B lymphocytes.
The Sle1ab genomic interval on murine chromosome 1 mediates the loss of immune tolerance to chromatin resulting in antinuclear Abs (ANA) production in the lupus-prone NZM2410 mouse. Global gene expression analysis was used to identify the molecular pathways that are dysregulated at the initiation of B lymphocyte autoimmunity in B6.Sle1ab mice. This analysis identified that STAT3 and ras-ERK signaling pathways are aberrantly activated in Sle1ab B lymphocytes, consistent with increased production of IL-6 by splenic B lymphocytes and monocytes in B6.Sle1ab mice. In vitro treatment of splenic mononuclear cells isolated from ANA-positive Sle1ab mice with anti-IL-6 Ab or AG490, an inhibitor of STAT3 signaling pathway, suppressed ANA production in short-term culture, indicating that this pathway was essential to the production of autoantibodies. In vivo treatment of ANA-positive B6.Sle1ab mice with the ras pathway inhibitor, perillyl alcohol, suppressed the increase of ANA. These findings identify IL-6 as a early key cytokine in Sle1ab-mediated disease development and indicate that the STAT3 and ras-ERK signaling pathways are potential therapeutic targets for treating systemic lupus erythematosus.
Liu
Kui
K
Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. kui.liu@utsouthwestern.edu
Liang
Chaoying
C
Liang
Zhiyan
Z
Tus
Katalin
K
Wakeland
Edward K
EK
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015850:Interleukin-6 / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000235:genetics* / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D018631:ras Proteins / Q000378:metabolism* / Q000502:physiology
D000974:Antibodies, Antinuclear; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D015850:Interleukin-6; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins