In the immune system, TGF-beta1 exerts two major functions, anti-inflammatory and immuno-suppressive effects. This work aims to investigate the molecular mechanisms involved in the regulation of the TGF-beta1 gene expression in CD4(+) T cells. The TGF-beta1 gene expresses three transcripts of 2.5, 1.9, and 1.4 kb. The 1.9 kb mRNA which has the highest translation activity was the major transcript. The relationship between T cell receptor (TCR) stimulation and the expression of the gene was investigated. TCR stimulation with a low dose of antigen peptide enhanced the gene expression, whereas a higher dose suppressed the expression. TCR stimulation activates PKC/MAPK and Ca2+ signaling pathways. PMA increased the gene expression, whereas ionomycin decreased the gene expression, markedly. The results indicate that Ca2+ signaling down-regulates TGF-beta1 gene expression. The molecular regulation of TGF-beta1 gene expression is unique When comparing to other cytokine genes which are generally activated by Ca2+ signaling. (C) 2004 Elsevier Inc. All rights reserved.