Enhanced IFN-γ Expression Research Articles

Bee venom modulates murine Th1/Th2 lineage development

Administration of bee venom (BV) elicits anti-inflammatory, anti-nociceptive and anti-allergic effects in various animal models. This study was designed to evaluate the direct effects of BV on helper T cell activities and on Th1/Th2 lineage development using both in vitro and in vivo conditions. In the Th1 skewed condition, BV increased the expression of IFN-γ mRNA and enhanced the expression of T-bet on purified CD4 + T cells from splenocytes of BALB/c mice. On the other hand, BV treatment did not alter the expression of IL-4 or GATA-3 in a Th2 driven environment. To elucidate the effects of BV on Th1/Th2 lineage development under in vivo conditions, BV was given by intraperitonial injection to BALB/c mice. It significantly increased the CD4 + T cell population and enhanced IFN-γ expression, while IL-4 transcripts were not altered upon in vivo activation using an anti-CD3 antibody injection. Taken together, these results imply that BV induces Th1 lineage development from CD4 + T cells by increasing the expression of a Th1-specific cytokine, IFN-γ. In addition, this result may be mediated by inducing a Th1-specific transcription factor, T-bet.

Evolutionarily conserved sequence elements that positively regulate IFN-gamma expression in T cells.

Our understanding of mechanisms by which the expression of IFN-gamma is regulated is limited. Herein, we identify two evolutionarily conserved noncoding sequence elements (IFNgCNS1 and IFNg CNS2) located approximately 5 kb upstream and approximately 18 kb downstream of the initiation codon of the murine Ifng gene. When linked to the murine Ifng gene (-3.4 to +5.6 kb) and transiently transfected into EL-4 cells, these elements clearly enhanced IFN-gamma expression in response to ionomycin and phorbol 12-myristate 13-acetate and weakly enhanced expression in response to T-bet. A DNase I hypersensitive site and extragenic transcripts at IFNgCNS2 correlated positively with the capacity of primary T cell subsets to produce IFN-gamma. Transcriptionally favorable histone modifications in the Ifng promoter, intronic regions, IFNgCNS2, and, although less pronounced, IFNgCNS1 increased as naïve T cells differentiated into IFN-gamma-producing effector CD8+ and T helper (TH) 1 T cells, but not into TH2 T cells. Like IFN-gamma expression, these histone modifications were T-bet-dependent in CD4+ cells, but not CD8+ T cells. These findings define two distal regulatory elements associated with T cell subset-specific IFN-gamma expression.