Anti-inflammatory activity of p-coumaryl alcohol-gamma-O-methyl ether is mediated through modulation of interferon-gamma production in Th cells

Abstract

p-Coumaryl alcohol-gamma-O-methyl ether (CAME) was isolated from Alpinia galanga and shown to contain a phenylpropanoid structure similar to p-coumaryl diacetate (CDA). CDA is known to have antioxidant and anti-inflammatory activity, but the biochemical activities of CAME are unknown. Inflammation is mediated by inflammatory cytokine production, in particular, by CD4+ T helper cells (Th cells), but it is unclear whether phenylpropanoids affect cytokine production in Th cells. In this study, we decided to investigate the functions of CAME and CDA in CD4+ Th cells. Mouse CD4+ Th cells were isolated from C57BL6 mice and stimulated with an antibody against T cell receptors in the presence of phenylpropanoids. Cytokine production was measured by elisa and intracellular cytokine staining. Gene knockout mice and tetracycline-inducible transgenic mice were used to examine the molecular mechanisms of phenylpropanoids on modulation of cytokine production. CAME potently reduced intracellular reactive oxygen species in Th cells, as does CDA. However, although CDA was cytotoxic, CAME selectively and potently suppresses interferon-gamma (IFN gamma) production in CD4+ Th cells, without toxicity. This effect was caused by attenuated expression of the transcription factor, T-box protein expressed in T cells (T-bet), and T-bet was essential for CAME to inhibit IFN gamma production in CD4+ Th cells. CAME selectively and substantially suppresses IFN gamma production in CD4+ Th cells by decreasing T-bet expression. As increased IFN gamma production by CD4+ Th cells can mediate inflammatory immune responses, a selective IFN gamma suppressor, such as CAME may be an effective, naturally occurring, compound for modulating inflammatory immune disorders.