TNF-alpha inhibits the CD3-mediated upregulation of voltage-gated K+ channel (Kv1.3) in human T cells.
A long term treatment of T cells with tumor necrosis factor alpha (TNF-alpha) paradoxically inhibits the immunologic responses to TCR/CD3 stimulation. The voltage-gated K(+) channels (K(v)) of T cells attracted attention as a pharmacological target for the treatment of autoimmune diseases. Here, the authors investigated the effects of TNF-alpha on the K(v) current (I(Kv)) and its upregulation by CD3 in human T cells. Acute treatment with TNF-alpha (10 min) temporarily decreased I(Kv) in Jurkat-T cells (cells subsequently recovered after treatment >12h), whereas CD3 stimulation for 24h increased I(Kv) amplitude more than two-fold. Furthermore, chronic pretreatment with TNF-alpha almost completely blocked the I(Kv) increase induced by CD3 stimulation. An immunoblot study confirmed an increase in the protein level of K(v) induced by CD3 stimulation, and its inhibition by TNF-alpha pretreatment. In addition, the facilitation of I(Kv) by CD3 stimulation and its inhibition by pretreatment with TNF-alpha were confirmed in freshly isolated human peripheral CD4(+) T cells, in which the voltage-dependence of I(Kv) was unaffected by TNF-alpha and/or CD3 stimulation. We conclude that the inhibition of CD3-induced K(v) upregulation by TNF-alpha might be associated with the paradoxical suppression of T cell function by TNF-alpha under conditions of chronic inflammation.
Pang
Bo
B
Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
Zheng
Haifeng
H
Shin
Dong Hoon
DH
Jung
Kyeong Cheon
KC
Ko
Jae Hong
JH
Lee
Ki Young
KY
Kang
Tong Mook
TM
Kim
Sung Joon
SJ
D017252:CD3 Complex / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D017252:CD3 Complex; D051664:Kv1.3 Potassium Channel; D014409:Tumor Necrosis Factor-alpha