TY - JOUR
T1 - Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus
AU - Wu, Tianfu
AU - Qin, Xiangmei
AU - Kurepa, Zoran
AU - Kumar, Kirthi Raman
AU - Liu, Kui
AU - Kanta, Hasna
AU - Zhou, Xin J.
AU - Satterthwaite, Anne B.
AU - Davis, Laurie S.
AU - Mohan, Chandra
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/8/1
Y1 - 2007/8/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI30398
DO - 10.1172/JCI30398
M3 - Article
C2 - 17641780
AN - SCOPUS:34547687662
SN - 0021-9738
VL - 117
SP - 2186
EP - 2196
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -