Ichikawa Daiju, Matsui Ayako, Imai Miwa, Sonoda Yoshiko, Kasahara Tadashi
Department of Biochemistry, Kyoritsu University of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Biol Pharm Bull. 2004 Sep;27(9):1353-8. doi: 10.1248/bpb.27.1353.
Interleukin-12 (IL-12) is a heterodimeric cytokine comprising p40 and p35 subunits produced mainly by monocytes and macrophages, and plays an essential role in the regulation of the differentiation of Th1 cells. Green tea polyphenols exhibit potent anti-oxidative activities and anti-inflammatory effects by modulating cytokine production. We investigated the effect of catechins on IL-12p40 production in murine macrophages induced by bacterial lipopolysaccharide (LPS). Pretreatment with several catechins at doses of 0.3-30 microM suppressed IL-12 p40 production by murine peritoneal exudate cells (PEC) and J774.1 cells in a dose-dependent manner. Decreases in protein production were primarily due to down-regulation of the transcription of IL-12p40 mRNA. Of the various catechins, (-)-epigallocatechin gallate (EGCG) was the most potent inhibitor, followed by (-)-gallocatechin gallate (GCG) and (-)-epicatechin gallate (ECG). EGCG inhibited LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), but not Jun N-terminal kinase (JNK), while EGCG augmented LPS-induced phosphorylation of p44/p42 extracellular signal-related kinase (ERK). In addition, both EGCG and GCG inhibited LPS-induced degradation of IkappaBalpha with concomitant inhibition of nuclear protein binding to NF-kappaB site and synthesis of IRF-1. These results suggest that gallate-containing catechins, particularly EGCG, inhibits LPS-induced IL-12p40 production in murine macrophages by inhibiting p38 MAPK while enhancing p44/p42 ERK, leading to the inhibition of IkappaBalpha degradation and NF-kappaB activation.
白细胞介素-12（IL-12）是一种异二聚体细胞因子，由主要由单核细胞和巨噬细胞产生的p40和p35亚基组成，在Th1细胞分化的调节中起重要作用。绿茶多酚通过调节细胞因子的产生表现出强大的抗氧化活性和抗炎作用。我们研究了儿茶素对细菌脂多糖（LPS）诱导的小鼠巨噬细胞中IL-12p40产生的影响。用0.3-30 microM剂量的几种儿茶素预处理可剂量依赖性地抑制小鼠腹腔渗出细胞（PEC）和J774.1细胞中IL-12 p40的产生。蛋白质产生的减少主要是由于IL-12p40 mRNA转录的下调。在各种儿茶素中，（-）-表没食子儿茶素没食子酸酯（EGCG）是最有效的抑制剂，其次是（-）-没食子儿茶素没食子酸酯（GCG）和（-）-表儿茶素没食子酸酯（ECG）。EGCG抑制LPS诱导的p38丝裂原活化蛋白激酶（MAPK）的磷酸化，但不抑制Jun N末端激酶（JNK），而EGCG增强LPS诱导的p44/p42细胞外信号相关激酶（ERK）的磷酸化。此外，EGCG和GCG均抑制LPS诱导的IkappaBalpha降解，同时抑制核蛋白与NF-kappaB位点的结合以及IRF-1的合成。这些结果表明，含没食子酸的儿茶素，特别是EGCG，通过抑制p38 MAPK同时增强p44/p42 ERK来抑制LPS诱导的小鼠巨噬细胞中IL-12p40的产生，从而导致IkappaBalpha降解和NF-kappaB活化的抑制。
