Progesterone and the Repression of Myometrial Inflammation: The Roles of MKP-1 and the AP-1 System.
Progesterone (P4) maintains uterine quiescence during pregnancy and its functional withdrawal is associated with increased prostaglandin synthesis and the onset of labor. In primary human myometrial cells, the glucocorticoid receptor (GR) rather than the P4 receptor mediates P4 antagonism of IL-1β-induced cyclooxygenase-2 (COX-2) expression, the rate-limiting enzyme in prostaglandin synthesis. We now report that P4 also acts via GR to induce MAPK phosphatase (MKP)-1 and knockdown of MKP-1 impairs the ability of P4 to repress IL-1β-dependent COX-2 induction. Microarray analysis revealed that P4 repressed preferentially activator protein-1-responsive genes in response to IL-1β. Consistent with these observations, we found that the ability of P4 to reduce c-Jun activation was lost upon GR as well as MKP-1 knockdown. Interestingly, c-Jun levels in human myometrial cells declined upon GR and MKP-1 knockdown, which suggests the presence of an activator protein-1 feedback loop. This is supported by our observation that c-Jun levels declined after an initial rise in primary myometrial cells treated with phorbol 12-myrisatate 13-acetate, a potent activator of c-Jun N-terminal kinase. Finally, we show that MKP-1 is an intermediate in P4-mediated repression of some but not all IL-1β-responsive genes. For example, P4 repression of IL11 and IRAK3 was maintained upon MKP-1 knockdown. Taken together, the data show that P4 acts via GR to drive MKP-1 expression, which in turn inhibits IL-1β-dependent c-Jun activation and COX-2 expression.
Imperial College Parturition Research Group (K.L., E.X.G., L.C., A.Y., S.R.S., M.R.J.), Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; Institute of Reproductive and Developmental Biology (KL.,. E.X.G., A.Y., S.R.S., P.R.B., M.R.J.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom; Obstetrics Department (L.C.), First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, People's Republic of China; and Reproductive Health (J.J.B.), University of Warwick, Coventry CV4 7AL, United Kingdom.
K
K
Lei
Imperial College Parturition Research Group (K.L., E.X.G., L.C., A.Y., S.R.S., M.R.J.), Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; Institute of Reproductive and Developmental Biology (KL.,. E.X.G., A.Y., S.R.S., P.R.B., M.R.J.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom; Obstetrics Department (L.C.), First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, People's Republic of China; and Reproductive Health (J.J.B.), University of Warwick, Coventry CV4 7AL, United Kingdom.
E X
EX
Georgiou
Imperial College Parturition Research Group (K.L., E.X.G., L.C., A.Y., S.R.S., M.R.J.), Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; Institute of Reproductive and Developmental Biology (KL.,. E.X.G., A.Y., S.R.S., P.R.B., M.R.J.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom; Obstetrics Department (L.C.), First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, People's Republic of China; and Reproductive Health (J.J.B.), University of Warwick, Coventry CV4 7AL, United Kingdom.
L
L
Chen
Imperial College Parturition Research Group (K.L., E.X.G., L.C., A.Y., S.R.S., M.R.J.), Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; Institute of Reproductive and Developmental Biology (KL.,. E.X.G., A.Y., S.R.S., P.R.B., M.R.J.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom; Obstetrics Department (L.C.), First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, People's Republic of China; and Reproductive Health (J.J.B.), University of Warwick, Coventry CV4 7AL, United Kingdom.
A
A
Yulia
Imperial College Parturition Research Group (K.L., E.X.G., L.C., A.Y., S.R.S., M.R.J.), Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; Institute of Reproductive and Developmental Biology (KL.,. E.X.G., A.Y., S.R.S., P.R.B., M.R.J.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom; Obstetrics Department (L.C.), First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, People's Republic of China; and Reproductive Health (J.J.B.), University of Warwick, Coventry CV4 7AL, United Kingdom.
S R
SR
Sooranna
Imperial College Parturition Research Group (K.L., E.X.G., L.C., A.Y., S.R.S., M.R.J.), Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; Institute of Reproductive and Developmental Biology (KL.,. E.X.G., A.Y., S.R.S., P.R.B., M.R.J.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom; Obstetrics Department (L.C.), First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, People's Republic of China; and Reproductive Health (J.J.B.), University of Warwick, Coventry CV4 7AL, United Kingdom.
J J
JJ
Brosens
Imperial College Parturition Research Group (K.L., E.X.G., L.C., A.Y., S.R.S., M.R.J.), Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; Institute of Reproductive and Developmental Biology (KL.,. E.X.G., A.Y., S.R.S., P.R.B., M.R.J.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom; Obstetrics Department (L.C.), First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, People's Republic of China; and Reproductive Health (J.J.B.), University of Warwick, Coventry CV4 7AL, United Kingdom.
P R
PR
Bennett
Imperial College Parturition Research Group (K.L., E.X.G., L.C., A.Y., S.R.S., M.R.J.), Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; Institute of Reproductive and Developmental Biology (KL.,. E.X.G., A.Y., S.R.S., P.R.B., M.R.J.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom; Obstetrics Department (L.C.), First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, People's Republic of China; and Reproductive Health (J.J.B.), University of Warwick, Coventry CV4 7AL, United Kingdom.
M R
MR
Johnson
D051546:Cyclooxygenase 2 / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008954:Models, Biological; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011374:Progesterone / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D011374:Progesterone; D051546:Cyclooxygenase 2; D054638:Dual Specificity Phosphatase 1