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Published on: August 14, 2008
Role of the K(Ca)3.1 K+ channel in auricular lymph node CD4+ T-lymphocyte function of the delayed-type
Susumu Ohya1, Erina Nakamura, Sayuri Horiba
1Department of Molecular & Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Insights
The intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) is upregulated in T-lymphocytes during delayed-type hypersensitivity (DTH). Blocking K(Ca)3.1 reduces DTH pathogenesis and T-lymphocyte proliferation, suggesting K(Ca)3.1 as a therapeutic target.
Area of Science:
- Immunology
- Cell Biology
- Channel Physiology
Background:
- The intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) plays a role in immune cell function by modulating membrane potential.
- Delayed-type hypersensitivity (DTH) is an immune response involving T-lymphocytes.
Purpose of the Study:
- To investigate the role of K(Ca)3.1 in the pathogenesis of oxazolone (Ox)-induced DTH.
- To examine K(Ca)3.1 expression and activity in CD4(+) T-lymphocytes from auricular lymph nodes (ALNs) of DTH model mice.
Main Methods:
- Real-time PCR, Western blotting, and flow cytometry were used to analyze K(Ca)3.1 expression and its regulators in ALN T-lymphocytes.
- Whole-cell patch clamp and voltage-sensitive dye imaging assessed K(Ca)3.1 activity.
- Selective K(Ca)3.1 blockers were administered to evaluate their effects on DTH.
Main Results:
- K(Ca)3.1a expression was significantly upregulated in CD4(+) T-lymphocytes of Ox-sensitized and challenged mice.
- Repressor element-1 silencing transcription factor (REST) expression was inversely correlated with K(Ca)3.1a levels.
- K(Ca)3.1 blockade inhibited CD4(+) T-lymphocyte proliferation and ameliorated DTH pathogenesis.
Conclusions:
- Upregulation of K(Ca)3.1a, potentially linked to REST downregulation, contributes to CD4(+) T-lymphocyte proliferation in DTH.
- K(Ca)3.1 represents a potential therapeutic target for allergic diseases like DTH.
Background And Purpose:
The intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) modulates the Ca(2+) response through the control of the membrane potential in the immune system. We investigated the role of K(Ca)3.1 on the pathogenesis of delayed-type hypersensitivity (DTH) in auricular lymph node (ALN) CD4(+) T-lymphocytes of oxazolone (Ox)-induced DTH model mice.
Experimental Approach:
The expression patterns of K(Ca)3.1 and its possible transcriptional regulators were compared among ALN T-lymphocytes of three groups [non-sensitized (Ox-/-), Ox-sensitized, but non-challenged (Ox+/-) and Ox-sensitized and -challenged (Ox+/+)] using real-time polymerase chain reaction, Western blotting and flow cytometry. KCa 3.1 activity was measured by whole-cell patch clamp and the voltage-sensitive dye imaging. The effects of K(Ca)3.1 blockade were examined by the administration of selective K(Ca)3.1 blockers.
Key Results:
Significant up-regulation of K(Ca)3.1a was observed in CD4(+) T-lymphocytes of Ox+/- and Ox+/+, without any evident changes in the expression of the dominant-negative form, K(Ca)3.1b. Negatively correlated with this, the repressor element-1 silencing transcription factor (REST) was significantly down-regulated. Pharmacological blockade of K(Ca)3.1 resulted in an accumulation of the CD4(+) T-lymphocytes of Ox+/+ at the G0/G1 phase of the cell cycle, and also significantly recovered not only the pathogenesis of DTH, but also the changes in the K(Ca)3.1 expression and activity in the CD4(+) T-lymphocytes of Ox+/- and Ox+/+.
Conclusions And Implications:
The up-regulation of K(Ca)3.1a in conjunction with the down-regulation of REST may be involved in CD4(+) T-lymphocyte proliferation in the ALNs of DTH model mice; and K(Ca)3.1 may be an important target for therapeutic intervention in allergy diseases such as DTH.
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