Sle1ab mediates the aberrant activation of STAT3 and Ras-ERK signaling pathways in B lymphocytes

Kui Liu, Chaoying Liang, Zhiyan Liang, Katalin Tus, Edward K. Wakeland

Research output: Contribution to journalArticle

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Abstract

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 res-ERK signaling pathways are potential therapeutic targets for treating systemic lupus erythematosus.

Original languageEnglish (US)
Pages (from-to)1630-1637
Number of pages8
JournalJournal of Immunology
Volume174
Issue number3
StatePublished - Feb 1 2005

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MAP Kinase Signaling System
B-Lymphocytes
Interleukin-6
perilla alcohol
Immune Tolerance
Chromosomes, Human, Pair 1
Autoimmunity
Systemic Lupus Erythematosus
Autoantibodies
Chromatin
Monocytes
Therapeutics
Cytokines
Gene Expression

ASJC Scopus subject areas

  • Immunology

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Sle1ab mediates the aberrant activation of STAT3 and Ras-ERK signaling pathways in B lymphocytes. / Liu, Kui; Liang, Chaoying; Liang, Zhiyan; Tus, Katalin; Wakeland, Edward K.

In: Journal of Immunology, Vol. 174, No. 3, 01.02.2005, p. 1630-1637.

Research output: Contribution to journalArticle

Liu, Kui ; Liang, Chaoying ; Liang, Zhiyan ; Tus, Katalin ; Wakeland, Edward K. / Sle1ab mediates the aberrant activation of STAT3 and Ras-ERK signaling pathways in B lymphocytes. In: Journal of Immunology. 2005 ; Vol. 174, No. 3. pp. 1630-1637.
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