Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus

Tianfu Wu, Xiangmei Qin, Zoran Kurepa, Kirthi Raman Kumar, Kui Liu, Hasna Kanta, Xin J. Zhou, Anne B. Satterthwaite, Laurie S. Davis, Chandra Mohan

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Though B cells play key roles in lupus pathogenesis, the molecular circuitry and its dysregulation in these cells as disease evolves remain poorly understood. To address this, a comprehensive scan of multiple signaling axes using multiplexed Western blotting was undertaken in several different murine lupus strains. PI3K/AKT/mTOR (mTOR, mammalian target of rapamycin), MEK1/Erk1/2, p38, NF-κB, multiple Bcl-2 family members, and cell-cycle molecules were observed to be hyperexpressed in lupus B cells in an age-dependent and lupus susceptibility gene-dose-dependent manner. Therapeutic targeting of the AKT/mTOR axis using a rapamycin (sirolimus) derivative ameliorated the serological, cellular, and pathological phenotypes associated with lupus. Surprisingly, the targeting of this axis was associated with the crippling of several other signaling axes. These studies reveal that lupus pathogenesis is contingent upon the activation of an elaborate network of signaling cascades that is shared among genetically distinct mouse models and raise hope that targeting pivotal nodes in these networks may offer therapeutic benefit.

Original languageEnglish (US)
Pages (from-to)2186-2196
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number8
DOIs
StatePublished - Aug 1 2007

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Sirolimus
B-Lymphocytes
Hope
Phosphatidylinositol 3-Kinases
Cell Cycle
Western Blotting
Phenotype
Therapeutics
Genes

ASJC Scopus subject areas

  • Medicine(all)

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Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. / Wu, Tianfu; Qin, Xiangmei; Kurepa, Zoran; Kumar, Kirthi Raman; Liu, Kui; Kanta, Hasna; Zhou, Xin J.; Satterthwaite, Anne B.; Davis, Laurie S.; Mohan, Chandra.

In: Journal of Clinical Investigation, Vol. 117, No. 8, 01.08.2007, p. 2186-2196.

Research output: Contribution to journalArticle

Wu, Tianfu ; Qin, Xiangmei ; Kurepa, Zoran ; Kumar, Kirthi Raman ; Liu, Kui ; Kanta, Hasna ; Zhou, Xin J. ; Satterthwaite, Anne B. ; Davis, Laurie S. ; Mohan, Chandra. / Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 8. pp. 2186-2196.
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