Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis.
OBJECTIVE
Endometriosis accompanies local inflammatory reactions in the peritoneal cavity. We examined the phosphorylation of mitogen-activated protein kinases (MAPKs), i.e. extracellular signal-regulated kinase (ERK), p38 MAPK (p38) and c-Jun N-terminal kinase (JNK) in endometriotic stromal cells, and their possible pathophysiological roles in endometriosis in relation to proinflammatory substances.


METHODS
Endometriotic stromal cells were isolated from endometriomas and were cultured for the experiments. Phosphorylation of MAPKs in endometriotic stromal cells treated with interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha and H(2)O(2) were examined by Western blot analysis. Effects of PD98059, SB202190 and SP600125 (inhibitors of ERK, p38 and JNK, respectively) on IL-1beta-induced secretion of IL-6 and IL-8, and on IL-1beta-induced expression of cyclo-oxygenase-2 (COX-2) in endometriotic cells were studied. In addition, eutopic endometrial tissues were collected, and the phosphorylation rate of p38 in eutopic endometrial tissues and endometriotic tissues were determined.


RESULTS
IL-1beta, TNFalpha and H(2)O(2) stimulated the phosphorylation of ERK, p38 and JNK, while the total amounts of proteins of the respective MAPKs were virtually the same compared with those in the unstimulated controls. Both SB202190 and SP600125 suppressed IL-1beta-induced secretion of IL-6 and IL-8, and PD98059 suppressed IL-1beta-induced secretion of IL-8. Both SB202190 and PD98059 suppressed IL-1beta-induced expression of COX-2 in endometriotic cells. The p38 phosphorylation rates in the endometriotic tissues were significantly higher than those in the eutopic endometrial tissues of the same patients.


CONCLUSIONS
Given the current theory that inflammatory changes are involved in the progression of endometriosis, MAPKs could play as pivotal intracellular signal transducers in endometriotic cells, and thus have a pathophysiological role in the disease.
Yoshino
Osamu
O
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo.
Osuga
Yutaka
Y
Hirota
Yasushi
Y
Koga
Kaori
K
Hirata
Tetsuya
T
Harada
Miyuki
M
Morimoto
Chieko
C
Yano
Tetsu
T
Nishii
Osamu
O
Tsutsumi
Osamu
O
Taketani
Yuji
Y
D000873:Anthracenes / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004715:Endometriosis / Q000378:metabolism / Q000503:physiopathology*; D004717:Endometrium / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006861:Hydrogen Peroxide; D007375:Interleukin-1; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000201:enzymology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
D000873:Anthracenes; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D006861:Hydrogen Peroxide; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C432165:pyrazolanthrone; C496540:PTGS2 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one