Abstract | 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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Authors | Susumu Ohya, Erina Nakamura, Sayuri Horiba, Hiroaki Kito, Miki Matsui, Hisao Yamamura, Yuji Imaizumi |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 169
Issue 5
Pg. 1011-23
(Jul 2013)
ISSN: 1476-5381 [Electronic] England |
PMID | 23594188
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2013 The British Pharmacological Society. |
Chemical References |
- Adjuvants, Immunologic
- Intermediate-Conductance Calcium-Activated Potassium Channels
- Kcnn4 protein, mouse
- Potassium Channel Blockers
- Pyrazoles
- RE1-silencing transcription factor
- Repressor Proteins
- TRAM 34
- Oxazolone
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Topics |
- Adjuvants, Immunologic
- Animals
- CD4-Positive T-Lymphocytes
(immunology, physiology)
- Cell Cycle
(drug effects)
- Disease Models, Animal
- Ear Auricle
(immunology)
- Hypersensitivity, Delayed
(chemically induced, immunology, physiopathology)
- Intermediate-Conductance Calcium-Activated Potassium Channels
(antagonists & inhibitors, immunology, physiology)
- Lymph Nodes
(immunology)
- Male
- Mice, Inbred BALB C
- Oxazolone
- Potassium Channel Blockers
(pharmacology)
- Pyrazoles
(pharmacology)
- Repressor Proteins
(immunology)
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