TNF-alpha inhibits the CD3-mediated upregulation of voltage-gated K(+) channel (K(v)1.3) in human T cells

Abstract

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 >12 h) whereas CD3 stimulation for 24 h 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. (C) 2009 Elsevier Inc. All rights reserved