Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus
Tianfu Wu, … , Laurie S. Davis, Chandra Mohan
Tianfu Wu, … , Laurie S. Davis, Chandra Mohan
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2186-2196. https://doi.org/10.1172/JCI30398.
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Research Article Immunology

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

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.

Authors

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

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Figure 7

Activation status of AKT and Erk1/2 in total splenic B cells and resting follicular B cells.

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Activation status of AKT and Erk1/2 in total splenic B cells and resting...
Anti-B220 bead-purified splenic B cells (A) and purified follicular splenic B cells obtained by flow cytometry–based cell-sorting (B) were isolated from 2-month-old female B6 and B6.Sle1z mice. Following an initial stimulation with a lower concentration of anti-IgM F(ab′)2 (1 μg/ml) for 48 hours, cells were either immediately lysed or were reexposed to a higher concentration of anti-IgM F(ab′)2 (10 μg/ml) for 5 minutes or 24 hours and then lysed. Lysates were electrophoresed and blotted using antibodies against the total or phosphorylated forms of AKT and Erk1/2. The mean band intensity values as analyzed by ImageJ are indicated below each band.