Involvement of ERK AND p38 MAP kinase in AAPH-induced COX-2 expression in HaCaT cells.
Cyclooxygenase-2 (COX-2) appears to play an important role in inflammation and carcinogenesis, and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) is a hydrophilic azo compound known to generate free radicals. Because reactive oxygen species (ROS) are known to elevate COX-2 expression, we evaluated the effect of AAPH on the expression of COX-2 in a human keratinocyte cell line, HaCaT. When cells were exposed to AAPH, marked COX-2 induction was observed. To clarify the signaling mechanism involved, we next investigated the effects of AAPH upon three major subfamilies of the mitogen-activated protein kinases (MAPKs). AAPH caused an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal kinase (JNK). Furthermore, we found that PD98059, an ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, diminished AAPH-induced COX-2 expression and PGE(2) production, whereas JNK inhibitor did not suppress COX-2 expression or PGE(2) production by AAPH. These findings suggest that the ERK and p38 MAPK pathways, but not the JNK pathway, are involved in AAPH-induced inflammatory progression. In addition, we found that both the water-soluble Vitamin E derivative, Trolox, and the green tea constituent, (-)-epigallocatechin gallate (EGCG), diminished AAPH-induced COX-2 expression and p38 activation.
Department of Dermatology, Seoul National University, Bundang Hospital, 300 Gumi-Dong, Bundang-Gu, Seongnam-Si, Kyoungki-Do 463-707, South Korea.
Yong
Y
Cui
Dong-Seok
DS
Kim
Seo-Hyoung
SH
Park
Jin-A
JA
Yoon
Soon-Kyum
SK
Kim
Sun-Bang
SB
Kwon
Kyoung-Chan
KC
Park
D000578:Amidines / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000201:enzymology*; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000578:Amidines; D002839:Chromans; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016166:Free Radical Scavengers; D007093:Imidazoles; D007527:Isoenzymes; D008565:Membrane Proteins; D011725:Pyridines; C046728:2,2'-azobis(2-amidinopropane); D002392:Catechin; C045651:epigallocatechin gallate; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone; C093642:SB 203580; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one