Endometrial stromal cells undergoing decidualization down-regulate their properties to produce proinflammatory cytokines in response to interleukin-1 beta via reduced p38 mitogen-activated protein kinase phosphorylation.
The decidualized endometrium plays a role in regulating trophoblast invasion for successful implantation and maintenance of pregnancy. IL-1 beta, a proinflammatory cytokine, has been suggested to play a role in this process. Recently, several lines of evidence indicate the importance of p38 MAPK in various inflammatory responses. We investigated whether endometrial stromal cells (ESC) change their inflammatory responses to IL-1 beta as related to p38 MAPK phosphorylation during the process of decidualization. ESC were decidualized by the treatment with progesterone for 9 d, as determined as such by an increase in the production of prolactin and cAMP by the cells. Whereas IL-1 beta increased the production of IL-6, IL-8, and monocyte chemotactic protein-1, and expression of cyclooxygenase-2 mRNA in ESC cultured without treatment, the stimulatory effects of IL-1 beta were reduced in the decidualized cells. Treatment with SB202190, a p38 MAPK inhibitor, also reduced the stimulatory effects of IL-1 beta in nondecidualized ESC. P38 MAPK phosphorylation was increased by IL-1 beta in nondecidualized ESC, whereas the IL-1 beta-induced increase was suppressed in the decidualized cells. Treatment with 8-bromo-cAMP reduced IL-1 beta-induced phosphorylation of p38 MAPK in nondecidualized ESC. In contrast, treatment with H89, a protein kinase A inhibitor, reversed a reduction in IL-1 beta-induced p38 MAPK phosphorylation in the decidualized cells. In summary, decidualization seems to be a process during which endometrial cells diminish their response to IL-1 beta, a known key factor for implantation, leading to the down-regulation of inflammation-like events, which may be relevant to controlled trophoblast invasion. The altered property of decidualized cells is thought to be caused by attenuation of IL-1 beta-induced p38 MAPK phosphorylation in a way that involves the activation of the cAMP/protein kinase A pathway.
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655,Japan.
Osamu
O
Yoshino
Yutaka
Y
Osuga
Yasushi
Y
Hirota
Kaori
K
Koga
Tetsuya
T
Hirata
Tetsu
T
Yano
Takuya
T
Ayabe
Osamu
O
Tsutsumi
Yuji
Y
Taketani
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis*; D003656:Decidua / Q000502:physiology*; D004717:Endometrium / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007527:Isoenzymes / Q000235:genetics; D007546:Isoquinolines / Q000494:pharmacology; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011374:Progesterone / Q000494:pharmacology; D011388:Prolactin / Q000096:biosynthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017154:Stromal Cells / Q000502:physiology*; D013449:Sulfonamides; D048051:p38 Mitogen-Activated Protein Kinases
D018932:Chemokine CCL2; D016207:Cytokines; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D007527:Isoenzymes; D007546:Isoquinolines; D008565:Membrane Proteins; D012333:RNA, Messenger; D013449:Sulfonamides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011374:Progesterone; D011388:Prolactin; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide