Regulation of uterine collagenase gene expression: interactions between serotonin and progesterone

Wilcox, Brian D.; Rydelek-Fitzgerald, Laura; Jeffrey, John J.

doi:10.1016/0303-7207(94)90220-8

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…Serotonin up-regulated genes include IL-1 (12), IL-6, 3 transin, and 92 kDa gelatinase, 2 while types I and III collagen, fibronectin, and ␣ 2 -macroglobulin are down-regulated by serotonin (11,13). While our previous studies have focused on the transcriptional regulation and enzymatic activity of MMP-13 (11,15,37), here we have extended those observations to the level of immunoreactive protein. The results of this study further clarify the signaling mechanisms by which serotonin, acting through the 5-HT 2A receptor, mediate the production of MMP-13 and demonstrate that phospholipase C, its downstream effector PKC and the MAP kinase cascade are integral components in this cell system.…”

Section: Discussionmentioning

confidence: 67%

“…Specifically, while the serotonin-dependent upregulated genes, MMP-13, transin, 92 kDa gelatinase, IL-1, and IL-6, appear to require IL-1, the down-regulated genes, types I and III collagen, fibronectin, and ␣ 2 -macroglobulin, are independent of IL-1 influence. Furthermore, phorbol esters, known activators of protein kinase C (PKC), mimic the effects of serotonin on the serotonin-dependent-induced genes while having no effect on the serotonin-dependent down-regulated genes (13,15). Conversely, 8-bromoadenosine 3Ј:5Ј-cyclic monophosphate (8-bromo-cyclic AMP) mimics the effects of serotonin on the negatively regulated gene products for type I collagen and ␣ 2 -macroglobulin (11,13).…”

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confidence: 99%

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Serotonin-induced MMP-13 Production Is Mediated via Phospholipase C, Protein Kinase C, and ERK1/2 in Rat Uterine Smooth Muscle Cells

Shum

Melendez

Jeffrey

2002

Journal of Biological Chemistry

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Serotonin (5-hydroxytryptamine; 5-HT), acting via the 5-HT 2A receptor, up-regulates the transcription and production of interstitial collagenase (matrix metalloproteinase-13; MMP-13), a critical enzyme responsible for maintaining the integrity of the uterus, after parturition. Serotonin treatment of rat uterine myometrial smooth muscle cells induced inositol phosphate (IP) turnover, which was abolished by the 5-HT 2A receptorspecific antagonists ketanserin and spiperone. The phospholipase C (PLC) inhibitors U73122 and D609 attenuated serotonin-mediated-IP turnover with a corresponding inhibition of MMP-13 protein production. Subsequent recovery of both MMP-13 protein expression and IP generation was seen following the removal of D609. Protein kinase C (PKC) activators, the diacylglycerol analogue 1,2-dioctanoyl-sn-glycerol and phorbol myristate acetate (PMA), mimicked the effect of serotonin on MMP-13 protein expression; prolonged PMA treatment (which down-regulates PKC) lowered MMP-13 protein levels. The PKC-specific inhibitors bisindolylmaleimide I, calphostin C, CGP 41251, and the PKC␦-selective inhibitor rottlerin were able to suppress serotonin up-regulation of MMP-13. Furthermore, the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 blocked serotonin-dependent activation of p44/42 MAPK (pERK1/2), a downstream effector of PKC and also down-regulated MMP-13 protein expression. Similarly, calphostin C and rottlerin depressed activation of p44/42 MAPK. From these studies, serotonin, binding through the 5-HT 2A receptor, initiates a signaling cascade whereby stimulation of PLC leads to the activation of PKC and subsequently the ERK1/2 pathway, which ultimately results in MMP-13 production.The maintenance of the three-dimensional architecture of the mammalian uterus is carefully regulated during pregnancy and after parturition. Production of fibrillar collagens (Types I and III) is up-regulated 10-fold in the uterus during pregnancy (1, 2). These collagens possess a rigid superhelical structure, which is responsible for providing the tensile strength necessary to accommodate the force exerted by the growing fetus. After parturition, a precisely programmed non-necrotic and non-inflammatory process of connective tissue remodeling occurs, which results in the rapid and dramatic degradation of the collagen amassed and returns the uterus to reproductive competence (3). This transition is initiated by the enzyme interstitial collagenase (matrix metalloproteinase-13; MMP-13), 1 a member of the matrix metalloproteinase family. It acts as not only the rate-limiting step but also the committed step in the catalysis of the degradation of extracellular collagen (4, 5). The expression of MMP-13 occurs during postpartum involution and is not present either during the pregnancy or even within hours prior to parturition. The myometrial smooth muscle cell of the uterus has been identified not only as the source for MMP-13 (6) but also that of its natural substrate, collagen (7). Thus, the myometrial smooth muscle...

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Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

Serotonin-induced MMP-13 Production Is Mediated via Phospholipase C, Protein Kinase C, and ERK1/2 in Rat Uterine Smooth Muscle Cells

Shum

Melendez

Jeffrey

2002

Journal of Biological Chemistry

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“…Previous investigators interested in matrix-degrading enzymes in uterine tissue have focused attention on the process of postpartum uterine involution in laboratory animal models. [23][24][25][26][27][28][29] To our knowledge, our experiments represent the first characterization of expression of these enzymes in a human uterine smooth muscle cell system. Our findings clearly demonstrate that human CSMC in culture can express a repertoire of proteinases that can hydrolyze the main constituents of the cervical extracellular matrix, including fibrillar collagens (MMP-1) and elastins (MMP-9 and cathepsin S).…”

Section: Discussionmentioning

confidence: 99%

Pro-Inflammatory Cytokines Induce Expression of Matrix-Metabolizing Enzymes in Human Cervical Smooth Muscle Cells

Watari

DiSanto

et al. 1999

The American Journal of Pathology

164

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The process of cervical ripening has been likened to an inflammatory reaction associated with the catabolism of cervical extracellular matrix by enzymes released from infiltrating leukocytes. We hypothesized that smooth muscle cells in the cervix also participate in this process and that pro-inflammatory cytokines act on cervical smooth muscle cells (CSMC) to provoke the expression of matrix-degrading enzymes. We treated primary cultures of human CSMC with tumor necrosis factor-␣ (TNF-␣) and examined expression of the elastinolytic enzyme , cathepsin S, the collagen metabolizing matrix metalloproteinases (MMP)-1 , -3 , -9 , and the tissue inhibitor of metalloproteinase (TIMP)-1 and -2. A time course analysis revealed that 10 ng/ml of TNF-␣ induced cathepsin S, MMP-1 , -3 , and -9 mRNA expression with the maximal response observed after 24 -48 hours. TNF-␣ induced cathepsin S , MMP-1 , -3 , and -9 mRNA expression in a dose-dependent manner: the maximal effect was observed at a concentration of 10 ng/ml , with appreciable increases observed at concentrations of 0.1 to 1.0 ng/ml. In contrast , TIMP-1 and -2 mRNAs were not significantly increased by TNF-␣ treatment. Interleukin-1␤ produced a pattern of gene expression in the CSMC similar to that observed following TNF-␣ treatment. Western blot analysis and zymography confirmed the induction of proMMP-1 , -3 , and -9 in response to TNF-␣, but MMP-2 immunoreactivity and zymographic activity were unaffected. TNF-␣ increased secretion of procathepsin S , but did not affect TIMP-1 and reduced TIMP-2 production. We conclude that CSMC are targets of pro-inflammatory cytokines, which induce a repertoire of enzymes capable of degrading the cervical extracellular matrix. The induction of these enzymes may facilitate the normal ripening of the cervix at term and participate in the The human cervix is composed primarily of connective tissue consisting mainly of fibrillar collagens, elastin, and glycosaminoglycans.

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“…An imbalance of collagen synthesis and degradation by MMP in the vascular wall have an important role in the pathogenesis of atherosclerosis (4). An altered response to estrogens and/or progestins may contribute to this imbalance, since these sex steroids are known to regulate collagen synthesis and MMP activity in reproductive organs (19,29) and in large and small vascular beds (30), including the renal glomerulus (7,17,26).The development of cultured aortic smooth muscle cells (ASMC) now provides the means to dissect their contribution to the susceptibility and resistance to atherosclerosis, in part by studying the molecular mechanisms involved in the regulation of collagen synthesis and MMP activity by sex hormones.Hormone replacement therapy (HRT), consisting of estrogens and progestins, had been advocated for the primary and secondary prevention of atherosclerosis in postmenopausal women on the basis of observational data. Unexpectedly, the Heart and Estrogen/progestin Replacement Study (HERS and HERS II) and the Estrogen Replacement in Atherosclerosis trial (ERA) showed that HRT was not beneficial in women with established CHD (6, 9, 10).…”

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confidence: 99%

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Response to sex hormones differs in atherosclerosis-susceptible and -resistant mice

Potier

Karl

Elliot

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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; 10.1152/ajpendo. 00451.2002.-Genetic factors that determine the degree of susceptibility to atherosclerosis may also influence the effects of estrogens and progestins in arterial vessel disease. We examined and compared estrogen receptor (ER) and progesterone receptor (PR) expression and the effects of 17␤-estradiol (E 2) and progesterone (P) on collagen synthesis and matrix metalloproteinase (MMP) activities in the aortic arch and in cultured aortic smooth muscle cells (ASMC) of atherosclerosis-susceptible (C57Bl6/J, B6) or -resistant (C3H/HeJ, C3H) mice. ER␣, ER␤, and PR levels were higher in the aorta and ASMC of atherosclerosis-susceptible B6 mice. In transfection studies using an estrogen response element-driven reporter plasmid, E 2 elicited a Ͼ2-fold increase in luciferase activity in ASMC of B6 (B6-ASMC), which demonstrated the transcriptional activity of ER in atherosclerosis-susceptible cells. Importantly, the response of endogenous target genes to E 2 and P was different in B6-ASMC and C3H-ASMC. E2 decreased collagen synthesis but had no effect on MMP activities in B6-ASMC. P decreased MMP-2 and MMP-9 activity in B6-ASMC. In contrast, E 2 increased MMP-2 and decreased MMP-9 activity but had no effect on collagen synthesis in C3H-ASMC. P had no effect on collagen synthesis and MMP activity in C3H-ASMC. These differences in response to sex hormones may have important implications for women who receive hormone replacement therapy. vascular smooth muscle cells; estrogen receptor; progesterone receptor; matrix metalloproteinase; collagen ATHEROSCLEROSIS AND CORONARY HEART DISEASE (CHD) remain the major causes of morbidity and mortality in the United States (24). The development and progression of atherosclerosis are determined by genetic as well as environmental factors. The development of atherosclerosis is under the control of multiple genes in humans as well as in rodents. Paigen and colleagues (15,(21)(22)(23) found that inbred mouse strains differ significantly in their susceptibility to diet-induced atherosclerosis and thereby defined "atherosclerosis-susceptible or atherosclerosis-resistant genetic backgrounds." C57Bl6/J (B6) mice fed a high-fat diet develop conspicuous atherosclerotic lesions, whereas C3H/HeJ (C3H) mice are resistant to diet-induced atherosclerosis. Comparative analysis of these mouse models provides a unique opportunity to study the impact of the genetic background on the expression of female sex hormone receptors and their effects on molecules involved in the protection or progression of atherosclerosis such as collagens and matrix metalloproteinase (MMP). An imbalance of collagen synthesis and degradation by MMP in the vascular wall have an important role in the pathogenesis of atherosclerosis (4). An altered response to estrogens and/or progestins may contribute to this imbalance, since these sex steroids are known to regulate collagen synthesis and MMP activity in reproductive organs (19,29) and in large and small vascular beds (30), including the renal glomerulus (7,17,26)....

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Regulation of uterine collagenase gene expression: interactions between serotonin and progesterone

Cited by 12 publications

References 28 publications

Serotonin-induced MMP-13 Production Is Mediated via Phospholipase C, Protein Kinase C, and ERK1/2 in Rat Uterine Smooth Muscle Cells

Serotonin-induced MMP-13 Production Is Mediated via Phospholipase C, Protein Kinase C, and ERK1/2 in Rat Uterine Smooth Muscle Cells

Pro-Inflammatory Cytokines Induce Expression of Matrix-Metabolizing Enzymes in Human Cervical Smooth Muscle Cells

Response to sex hormones differs in atherosclerosis-susceptible and -resistant mice

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