Expression of TASK-2 and its upregulation by B cell receptor stimulation in WEHI-231 mouse immature B cells

2011 ◽  
Vol 300 (5) ◽  
pp. C1013-C1022 ◽  
Author(s):  
Joo Hyun Nam ◽  
Dong Hoon Shin ◽  
Haifeng Zheng ◽  
Dong-Sup Lee ◽  
Su Jung Park ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Single Channel ◽  
Calcineurin Inhibitors ◽  
Cell Receptor ◽  
Wehi 231 ◽  
Immature B Cells ◽  
Interfering Rna ◽  
First Time ◽  
Molecular Nature

Stimulation of B cell receptors (BCR ligation) induces apoptosis of immature B cells, which is critical to the elimination of self-reactive clones. In the mouse immature B cell line WEHI-231, the authors previously reported two types of background K+ channels with large (∼300 pS, LKbg) and medium (∼100 pS, MKbg) conductance in divalent cation-free conditions. While the authors have recently identified LKbg as TREK-2, the molecular nature of MKbg is unknown yet. In the present study, the authors found that BCR ligation markedly increased the background K+ conductance of WEHI-231. A single-channel study revealed that MKbg activity is increased by BCR ligation and that the biophysical properties (unitary conductance and pH sensitivity) of MKbg are consistent with those of TWIK-related acid-sensitive K+ channel 2 (TASK-2). The expression of TASK-2 and its upregulation by BCR ligation were confirmed by RT-PCR and immunoblot assays in WEHI-231. The BCR ligation-induced increase of K+ current was prevented by calcineurin inhibitors (cyclosporine A or FK506), and also by TASK-2-specific small interfering RNA (siRNA) transfection (si-TASK-2). Furthermore, si-TASK-2 attenuated the apoptosis of WEHI-231 caused by BCR ligation. TASK-2 activity and its mRNA were also confirmed in the primary splenic B cells of mouse. Summarizing, the authors report for the first time the expression of TASK-2 in B cells and surmise that the upregulation of TASK-2 by BCR ligation is associated with the apoptosis of immature B cells.

scholarly journals Apoptosis induced by the antigen receptor and Fas in a variant of the immature B cell line WEHI-231 and in splenic immature B cells

2001 ◽  
Vol 13 (4) ◽  
pp. 581-592 ◽  
Author(s):  
Maoxin Tim Tian ◽  
Chih-Hao Gilbert Chou ◽  
Anthony L. DeFranco
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Antigen Receptor ◽  
Wehi 231 ◽  
Immature B Cells

scholarly journals Prolactin Rescues Immature B-Cells from Apoptosis Induced by B-Cell Receptor Cross-Linking

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Rocio Flores-Fernández ◽  
Francisco Blanco-Favela ◽  
Ezequiel M. Fuentes-Pananá ◽  
Luis Chávez-Sánchez ◽  
Patricia Gorocica-Rosete ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Receptor Interaction ◽  
Cross Linking ◽  
Relative Expression ◽  
Wehi 231 ◽  
Immature B Cells ◽  
The Cross

Prolactin has an immunomodulatory effect and has been associated with B-cell-triggered autoimmune diseases, such as systemic lupus erythematosus (SLE). In mice that develop SLE, the PRL receptor is expressed in early bone marrow B-cells, and increased levels of PRL hasten disease manifestations, which are correlated with a reduction in the absolute number of immature B-cells. The aim of this work was to determine the effect of PRL in anin vitrosystem of B-cell tolerance using WEHI-231 cells and immature B-cells from lupus prone MRL/lpr mice. WEHI-231 cells express the long isoform of the PRL receptor, and PRL rescued the cells from cell death by decreasing the apoptosis induced by the cross-linking of the B-cell antigen receptor (BCR) as measured by Annexin V and active caspase-3. This decrease in apoptosis may have been due to the PRL and receptor interaction, which increased the relative expression of antiapoptotic Bcl-xL and decreased the relative expression of proapoptotic Bad. In immature B-cells from MRL/lpr mice, PRL increased the viability and decreased the apoptosis induced by the cross-linking of BCR, which may favor the maturation of self-reactive B-cells and contribute to the onset of disease.

scholarly journals Gαq-containing G proteins regulate B cell selection and survival and are required to prevent B cell–dependent autoimmunity

2010 ◽  
Vol 207 (8) ◽  
pp. 1775-1789 ◽  
Author(s):  
Ravi S. Misra ◽  
Guixiu Shi ◽  
Miguel E. Moreno-Garcia ◽  
Anil Thankappan ◽  
Michael Tighe ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
G Proteins ◽  
Tolerance Induction ◽  
Cell Receptor ◽  
Peripheral Tolerance ◽  
Systemic Autoimmune Disease ◽  
Intrinsic Defect ◽  
B Cell Tolerance ◽  
First Time

Survival of mature B cells is regulated by B cell receptor and BAFFR-dependent signals. We show that B cells from mice lacking the Gαq subunit of trimeric G proteins (Gnaq−/− mice) have an intrinsic survival advantage over normal B cells, even in the absence of BAFF. Gnaq−/− B cells develop normally in the bone marrow but inappropriately survive peripheral tolerance checkpoints, leading to the accumulation of transitional, marginal zone, and follicular B cells, many of which are autoreactive. Gnaq−/− chimeric mice rapidly develop arthritis as well as other manifestations of systemic autoimmune disease. Importantly, we demonstrate that the development of the autoreactive B cell compartment is the result of an intrinsic defect in Gnaq−/− B cells, resulting in the aberrant activation of the prosurvival factor Akt. Together, these data show for the first time that signaling through trimeric G proteins is critically important for maintaining control of peripheral B cell tolerance induction and repressing autoimmunity.

scholarly journals A Role for Interferon Regulatory Factor 4 in Receptor Editing

2008 ◽  
Vol 28 (8) ◽  
pp. 2815-2824 ◽  
Author(s):  
Simanta Pathak ◽  
Shibin Ma ◽  
Long Trinh ◽  
Runqing Lu
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Interferon Regulatory Factor ◽  
Receptor Editing ◽  
Regulatory Factor ◽  
Cell Stage ◽  
Immature B Cells ◽  
Interferon Regulatory Factor 4 ◽  
Secondary Rearrangement

ABSTRACT Receptor editing is the primary means through which B cells revise antigen receptors and maintain central tolerance. Previous studies have demonstrated that interferon regulatory factor 4 (IRF-4) and IRF-8 promote immunoglobulin light-chain rearrangement and transcription at the pre-B stage. Here, the roles of IRF-4 and -8 in receptor editing were analyzed. Our results show that secondary rearrangement was impaired in IRF-4 but not IRF-8 mutant mice, suggesting that receptor editing is defective in the absence of IRF-4. The role of IRF-4 in receptor editing was further examined in B-cell-receptor (BCR) transgenic mice. Our results show that secondary rearrangement triggered by membrane-bound antigen was defective in the IRF-4-deficient mice. Our results further reveal that the defect in secondary rearrangement is more severe at the immunoglobulin λ locus than at the κ locus, indicating that IRF-4 is more critical for the λ rearrangement. We provide evidence demonstrating that the expression of IRF-4 in immature B cells is rapidly induced by self-antigen and that the reconstitution of IRF-4 expression in the IRF-4 mutant immature B cells promotes secondary rearrangement. Thus, our studies identify IRF-4 as a nuclear effector of a BCR signaling pathway that promotes secondary rearrangement at the immature B-cell stage.

scholarly journals RasGRP1 Sensitizes an Immature B Cell Line to Antigen Receptor-induced Apoptosis

2004 ◽  
Vol 279 (19) ◽  
pp. 19523-19530 ◽  
Author(s):  
Benoit Guilbault ◽  
Robert J. Kay
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Wehi 231 ◽  
Induced Apoptosis

RasGRP1 is a guanine nucleotide exchange factor that activates Ras GTPases and is activated downstream of antigen receptors on both T and B lymphocytes. Ras-GRP1 provides signals to immature T cells that confer survival and proliferation, but RasGRP1 also promotes T cell receptor-mediated deletion of mature T cells. We used the WEHI-231 cell line as an experimental system to determine whether RasGRP1 can serve as a quantitative modifier of B cell receptor-induced deletion of immature B cells. A 2-fold elevation in RasGRP1 expression markedly increased apoptosis of WEHI-231 cells following B cell receptor ligation, whereas a dominant negative mutant of RasGRP1 suppressed B cell receptor-induced apoptosis. Activation of ERK1 or ERK2 kinases was not required for RasGRP1-mediated apoptosis. Instead, elevated RasGRP1 expression caused down-regulation of NF-κB and Bcl-xL, which provide survival signals counter-acting apoptosis induction by B cell receptor. Inhibition of NF-κB was sufficient to enhance B cell receptor-induced apoptosis of WEHI-231 cells, and ligation of co-stimulatory receptors that activate NF-κB suppressed the ability of RasGRP1 to promote B cell receptor-induced apoptosis. These experiments define a novel apoptosis-promoting pathway leading from B cell receptor to the inhibition of NF-κB and demonstrate that differential expression of RasGRP1 has the potential to modulate the sensitivities of B cells to negative selection following antigen encounter.

scholarly journals CTCF functions as a critical regulator of cell-cycle arrest and death after ligation of the B cell receptor on immature B cells

2003 ◽  
Vol 100 (2) ◽  
pp. 633-638 ◽  
Author(s):  
C.-F. Qi ◽  
A. Martensson ◽  
M. Mattioli ◽  
R. Dalla-Favera ◽  
V. V. Lobanenkov ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cycle Arrest ◽  
Immature B Cells

scholarly journals Receptor Editing Occurs Frequently during Normal B Cell Development

1998 ◽  
Vol 188 (7) ◽  
pp. 1231-1238 ◽  
Author(s):  
Marc W. Retter ◽  
David Nemazee
Keyword(s):  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Cell Receptor ◽  
Feedback Mechanism ◽  
Chain Gene ◽  
Allelic Exclusion ◽  
Receptor Editing ◽  
Light Chain Gene ◽  
Immature B Cells

Allelic exclusion is established in development through a feedback mechanism in which the assembled immunoglobulin (Ig) suppresses further V(D)J rearrangement. But Ig expression sometimes fails to prevent further rearrangement. In autoantibody transgenic mice, reactivity of immature B cells with autoantigen can induce receptor editing, in which allelic exclusion is transiently prevented or reversed through nested light chain gene rearrangement, often resulting in altered B cell receptor specificity. To determine the extent of receptor editing in a normal, non-Ig transgenic immune system, we took advantage of the fact that λ light chain genes usually rearrange after κ genes. This allowed us to analyze κ loci in IgMλ+ cells to determine how frequently in-frame κ genes fail to suppress λ gene rearrangements. To do this, we analyzed recombined VκJκ genes inactivated by subsequent recombining sequence (RS) rearrangement. RS rearrangements delete portions of the κ locus by a V(D)J recombinase-dependent mechanism, suggesting that they play a role in receptor editing. We show that RS recombination is frequently induced by, and inactivates, functionally rearranged κ loci, as nearly half (47%) of the RS-inactivated VκJκ joins were in-frame. These findings suggest that receptor editing occurs at a surprisingly high frequency in normal B cells.

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