Effect of various catechins on the IL-12p40 production by murine peritoneal macrophages and a macrophage cell line, J774.1.
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.
Ichikawa
Daiju
D
Department of Biochemistry, Kyoritsu University of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Matsui
Ayako
A
Imai
Miwa
M
Sonoda
Yoshiko
Y
Kasahara
Tadashi
T
D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D050856:Interferon Regulatory Factor-1; D018664:Interleukin-12 / Q000096:biosynthesis*; D053762:Interleukin-12 Subunit p40; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis; D021122:Protein Subunits / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D050856:Interferon Regulatory Factor-1; D053762:Interleukin-12 Subunit p40; C494258:Irf1 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D010750:Phosphoproteins; D021122:Protein Subunits; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D018664:Interleukin-12; D009569:Nitric Oxide; D002392:Catechin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases