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by Human Endometrial Stromal Cells Is Triggered during Menses and Dysfunctional Bleeding and Is Induced in Culture by Epithelial Interleukin-1 Released upon Ovarian Steroids WithdrawalCell Biology Unit (C.M.P., H.P.G.C., P.B.C., D.D., P.J.C., E.M., P.H.), de Duve Institute, and Department of Pathology (P.B.C., C.G., D.D., E.M.), Université catholique de Louvain, B-1200 Bruxelles, Belgium
Address all correspondence and requests for reprints to: Patrick Henriet, CELL Unit, de Duve Institute, UCL-75.41, 75 avenue Hippocrate, B-1200 Bruxelles, Belgium. E-mail: patrick.henriet{at}uclouvain.be.
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Abstract |
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is repressed by ovarian steroids. However, the control by estradiol (E) and progesterone (P) of endometrial IL-1 expression and bioactivity remains unknown.
Objective and Design: Variations of endometrial IL-1 mRNA and protein along the menstrual cycle and during dysfunctional bleeding were determined using RT-PCR, in situ hybridization, and immunolabeling. The mechanism of EP control was analyzed using culture of explants, laser capture microdissection, and purified cells. Data were compared with expression changes of IL-1β and IL-1 receptor antagonist.
Results: IL-1 is synthesized by epithelial cells throughout the cycle but E and/or P prevents its release. In contrast, endometrial stromal cells produce IL-1 only at menses and during irregular bleeding in areas of tissue breakdown. Stromal expression of IL-1, like that of MMP-1, is repressed by P (alone or with E) but triggered by epithelium-derived IL-1 released upon EP withdrawal.
Conclusions: Our experiments in cultured endometrium suggest that IL-1 released by epithelial cells triggers the production of IL-1 by stromal cells in a paracrine amplification loop to induce MMP-1 expression during menstruation and dysfunctional bleeding. All three steps of this amplification cascade are repressed by EP.
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Introduction |
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and IL-1β, their physiological antagonist, IL-1 receptor antagonist (IL-1Ra), and shared receptors, IL-1RI and IL-1RII. This system controls both implantation and menstrual tissue degradation.
The expression of matrix metalloproteinases (MMPs), including interstitial collagenase (MMP-1), is dramatically increased at the onset of menstruation (2, 3). Menstrual-like tissue lysis is reproduced in endometrial explants when deprived of ovarian steroids and is prevented by EP or MMP inhibitors (4). Several lines of evidence involve IL-1 in menstrual MMP production by endometrial stromal cells (ESCs). First, IL-1 stimulates MMP-1 expression by purified ESCs (5). Second, release of both IL-1 and MMP-1 occurs early in explants from menstrual samples, but later in nonmenstrual explants cultured without EP (6). Third, menstrual MMPs first appear in foci of ESCs surrounding glands, suggesting a paracrine stimulation by epithelial cells (7). Fourth, in coculture of purified endometrial epithelial and stromal cells, secretion of collagenase by ESCs requires paracrine stimulation by epithelial cell-derived IL-1 (6). A similar opposite control by IL-1 (induction) and EP (repression) was reported for stromal MMP-3 (8). Fifth, MMPs and IL-1 are both abundantly released in several pathologies of the female genital tract including dysfunctional endometrial bleeding (9, 10), endometriosis (11, 12), and tumors (13, 14, 15).
Taken together, these observations clearly suggest that regulation of IL-1 bioavailability modulates in time and space the global hormonal control of human endometrium shedding and bleeding. However, little is known on the control of IL-1 expression in the cycling endometrium, including its cellular origin (epithelial vs. stromal) and the influence of EP. Previous studies quantifying IL-1 protein led to contradictory results (12, 16) or were limited to culture media, which do not allow discriminating between effects on gene expression and cytokine release (6).
To decipher the control of IL-1 bioavailability in the human endometrium, IL-1 mRNA and protein were quantified and localized throughout normal cycle and during irregular bleeding episodes. The effects of ovarian steroids were analyzed in explants. Because IL-1 effects are influenced by competing ligands, the expression profiles of IL-1β and IL-1Ra were compared. Striking differences in the effects of EP on epithelial and stromal IL-1 were further analyzed in purified cell culture.
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Patients and Methods |
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The superficial layer of human endometrium was collected by gentle scraping from hysterectomy specimens of 120 patients not treated with ovarian steroids or from biopsies of nine irregularly bleeding patients (four under hormonal treatment) after informed consent. The Ethical Committee of our university approved the study. The tissue was divided into three parts. One part was fixed in 4% formaldehyde and embedded in paraffin for histological analysis and dating along the menstrual cycle. The theoretical 28-d cycle, starting with onset of menstrual bleeding (d 1), was divided into proliferative (d 6–14), secretory (d 15–27), and menstrual (d 28–5) phases. Another part was frozen at –20 C for ELISA or at –80 C in lysis buffer (SV Total RNA Isolation System; Promega, Madison, WI) for RNA extraction. The remaining tissue was cultured as explants or purified cells.
Explants were cultured for 24 h in DMEM (Life Technologies, Merelbeke, Belgium) supplemented with 0.3 µM 2-hydroxypropyl-β-cyclodextrin, alone as control vector or carrying 1 nM 17β-estradiol and 100 nM P (EP; Sigma-Aldrich, Bornem, Belgium). In some experiments, 8 µM cycloheximide (Sigma-Aldrich) was present throughout culture. After culture, explants were 1) fixed or frozen as above or 2) embedded in Tissue-Tek O.C.T tissue-freezing medium (Sakura, Zoeterwoude, The Netherlands) and frozen in liquid nitrogen-cooled isopentane for laser capture microdissection.
Endometrial epithelial and stromal cells were isolated by digestion with 1 mg/ml bacterial collagenase (type IA; Sigma-Aldrich), filtration through a 300-µm mesh, and retention (epithelial strips) or passage through a 30-µm filter (ESCs). Both cell types were adapted to culture (see figure legends) in DMEM-F12 medium with 10% fetal bovine serum supplemented with EP, 100 U/ml penicillin, and 100 µg/ml streptomycin (Life Technologies). Epithelial cells were further cultured for 24 h without serum and with Complete proteases inhibitors (1 tablet/50ml; Roche, Mannheim, Germany) in wells coated with 25 µg/ml type IV collagen (Sigma-Aldrich). ESCs were further cultured for 24 h 1) with or without 100 pg/ml recombinant human IL-1 or 2) with medium conditioned by epithelial cells, supplemented either with 5 µg/ml mouse monoclonal antibody neutralizing IL-1 (clone 4414,141; both from R&D Systems, Minneapolis, MN) or with 5 µg/ml irrelevant mouse monoclonal antibody (clone RPC5; Ancell, Bayport, MN). During these last 24 h of culture, epithelial cells and ESCs were subjected to maintenance or withdrawal of E and/or P.
The presence of E receptor- (ER) and of both P receptor (PR) isoforms PRA and PRB was examined by immunohistochemistry in cultured explants and cells (supplementary figure 1).
mRNA quantification
Total RNA was purified and reverse transcribed as described (17). Real-time PCR was performed as reported for β-actin (3) or using the qPCR Core kit (Eurogentec, Seraing, Belgium) with a MyiQ Single-Color Real-time PCR Detection System (Bio-Rad, Hercules, CA) and pairs of appropriate primers crossing over at least two exons (Life Technologies) (Table 1
). After a 5-min step at 95 C, cDNA was amplified through 40 two-step cycles at 95 C and 60 C, for 30 sec each, and SYBR Green fluorescence was measured. Data were analyzed using MyiQ System Software (version 1.0.410; Bio-Rad). Purified amplicons were used as quantification standards after cloning in pCR4-TOPO vector (Life Technologies). Each PCR experiment, run in duplicate, was validated as reported (3), including a single melting temperature after progressive amplicon heating. Values were normalized to β-actin mRNA levels, which do not vary during the menstrual cycle (17).
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Laser capture microdissection was performed on the PALM MicroBeam System (P.A.L.M. Microlaser Technologies, Bernried, Germany) as described (18). Typically, 20 slides were prepared per sample and about 50 microdissected glands or ESC foci were pooled separately. Extracted RNA was linearly amplified with the two-cycle amplification kit (Affymetrix, Santa Clara, CA), and 400 ng resulting cRNA was reverse transcribed with Thermoscript RT-PCR System (Life Technologies) using 3 µM forward primers for β-actin 2, IL-1, IL-1β, and IL-1Ra (Table 1
).
Protein and DNA quantification
Tissue samples, explants, and cells were homogenized in PBS containing 1% Tween 20 (PBS-Tween; Merck, Darmstadt, Germany). Total protein amounts were measured using bicinchoninic acid (Sigma), and DNA content was measured by spectrophotometry at 460 nm in the presence of 0.5 µg/ml diamino-2-phenyl-indole (Sigma). Concentrations of IL-1, IL-1β, and IL-1Ra were measured by ELISA using Quantikine Immunoassays (R&D Systems). For controlled extracellular proteolysis experiments, explants were incubated with a protease mixture (9 mg/ml Liberase Blendzyme 4; Roche) at 37 C for 30 min, after which proteolysis-resistant material was collected by centrifugation, washed, and homogenized in PBS-Tween supplemented with the Complete proteases inhibitors at 4-fold the recommended concentration. To assess cell integrity, the 20S proteasome subunit was quantified by ELISA (19).
Histological analysis
Immunostaining was performed by indirect peroxidase detection, as described (20), using mouse anti-IL-1 (clone 4414,141; 3.3 µg/ml), anticytokeratins (clones AE1/AE3, 1.5 µg/ml; DakoCytomation, Glostrup, Denmark) or nonrelevant mouse antibody, clone E13 (Argene Biosoft, Varhiles, France) or clone RPC5, as negative control. For cell type identification, serial sections were double immunolabeled for IL-1 (as above) and for CD10 (clone 56C6, 2 µg/ml; Biocare Medical, Concord, CA), CD45 (clones PD7/26 and 2B11, 1 µg/ml; DakoCytomation), CD56 (clone 1B6, 0.9 µg/ml; Novocastra, Newcastle upon Tyne, UK) or CD68 (clone PG-M1, 5 µg/ml; DakoCytomation) using alkaline phosphatase-coupled secondary antibody as described (20). Collagen fibers were stained with silver (4). In situ hybridization of IL-1 mRNA was performed as reported (3), using oligonucleotides described in Table 1. Hybridization temperature was adjusted to 40 C. The absence of signal using a control sense probe was verified in every experiment.
Statistical analyses
Statistical significance was tested using Kruskal-Wallis ANOVA followed by Wilcoxon two-sample or matched-pair test, as appropriate. Differences were considered significant for P < 0.05.
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Results |
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, IL-1β, and IL-1Ra in the cycling human endometrium and cultured explants
IL-1, IL-1β, and IL-1Ra mRNA was measured by real-time RT-PCR and normalized to β-actin mRNA (3, 17, 20) in 78 endometrial samples collected throughout the menstrual cycle (Fig. 1, A, E, and I). Corresponding proteins were quantified in 39 of these and 15 other samples (Fig. 1, C, G, and K). mRNAs and proteins were detected in all samples, except for IL-1β protein, which was below detection limit in eight of 24 secretory and nine of 19 proliferative endometria, despite similar ELISA sensitivity for both IL-1R agonists.
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protein. Post hoc Wilcoxon test confirmed a moderate increase from secretory to menstrual phase for IL-1 mRNA (2.7-fold) and IL-1Ra mRNA (4.3-fold) and significant decrease from menstrual to proliferative phase (between 2.3- and 20-fold) for the three mRNAs and IL-1 protein. IL-1β mRNA increased from proliferative to secretory phase (5.6-fold).
Altogether, changes along the menstrual cycle were thus moderate, arguing against a major global control by ovarian steroids. This was tested by culturing explants from 10 secretory and 10 proliferative endometria with or without combined EP for 24 h. In the absence of EP, IL-1 and IL-1β amounts increased upon culture to reach values in the upper range of, or even above, corresponding noncultured samples (Fig. 1, B, D, F, and H), but IL-1Ra was comparable before and after culture (Fig. 1, J and L). EP addition slightly inhibited (
2-fold) the increase of IL-1 protein and IL-1β mRNA and protein in proliferative cultures. Thus, both in vivo and ex vivo data indicated that ovarian steroids are global minor repressors of IL-1 and IL-1β expression in total endometrial tissues.
Differential control of IL-1 expression by ovarian steroids in epithelial and stromal cells
To identify cell-type-specific control of IL-1 and IL-1β expression, glands and stroma were separated by laser capture microdissection from three proliferative explant cultures and analyzed by quantitative RT-PCR (Fig. 1, M–O). In the absence of hormones, mRNA amounts of IL-1 and IL-1Ra were comparable in stroma and glands, but those of IL-1β were much lower in glands (>25-fold), reaching the limit of detection. EP strongly repressed IL-1 mRNA in the stroma (14-fold) but not in glands. IL-1Ra mRNA was at similar levels in both cell types, without consistent regulation by EP.
Localization of IL-1 mRNA and protein in the cycling endometrium and during dysfunctional bleeding
Cellular origin and cell-type-specific control of IL-1 expression were further explored in noncultured endometria by in situ hybridization (Fig. 2, A–D) and immunohistochemistry (Fig. 2, E–H). IL-1 mRNA and protein were detected in epithelial cells of all samples, irrespective of the cycle phase. In contrast, the stromal compartment showed no signal during proliferative and secretory phases but was strongly and diffusely labeled in all menstrual samples. Immunohistochemical identification of ESCs clearly indicated that most IL-1-producing cells were fibroblasts (Fig. 2, I–L), but contribution by hematopoietic cells could not be excluded.
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release was previously observed during dysfunctional endometrial bleeding (9), we also immunolocalized IL-1 in biopsies collected during irregular bleeding episodes from nine patients. Silver staining allowed us to distinguish preserved (Fig. 2M) and degraded areas (Fig. 2O). Contrasting with comparable epithelial staining in preserved and degraded areas, a strong menstrual-like IL-1 signal was detected in degraded stromal areas of all samples tested (Fig. 2P) but was absent in adjacent preserved areas (Fig. 2N).
Ovarian steroids not only repress IL-1 expression by ESCs but also prevent IL-1 release by epithelial cells
The hypothesis that cyclic changes in ovarian steroids are responsible for the cell-type-specific control of IL-1 was addressed by explant cultures (Fig. 3, A–D). As in noncultured samples, epithelial cells were stained for both IL-1 mRNA and protein in all explants, irrespective of hormone addition. By contrast, and in agreement with results on microdissected explants, IL-1 mRNA and protein labeling in ESCs was weak or undetectable in explants cultured with EP but was strong in explants cultured without EP. To address whether EP could regulate epithelial IL-1 bioavailability by controlling its release into the extracellular space, nonmenstrual explants were cultured in the presence of the translation inhibitor cycloheximide so as to block IL-1 synthesis and restrict the analysis to the fate of IL-1 present in cells before culture (Fig. 3, E–J). Epithelial IL-1 immunostaining was preserved when EP were combined with cycloheximide (Fig. 3E) but totally disappeared in explants cultured with cycloheximide alone (Fig. 3F), suggesting that IL-1 was released and/or degraded in the absence of hormones. Excellent preservation of cytokeratin staining argued against damage of epithelial cells by these treatments (Fig. 3, G and H). Surprisingly, in remarkable contrast with immunostaining, total IL-1 contents measured by ELISA in lysates of cycloheximide-treated explants were identical regardless of EP addition (Fig. 3I). Moreover, IL-1 amounts measured in conditioned media (not shown) did not increase in the absence of EP (both means = 1.1% of IL-1 assayed in tissue; n = 11). These data suggested inadequate retention or insufficient detection of extracellular IL-1 when using immunohistochemistry. To further discriminate between intracellular and extracellular IL-1, extracellular matrix and mingled proteins were degraded by subjecting explants to limited protease digestion after their culture in the presence of cycloheximide with or without EP. Amounts of preserved IL-1 protein were measured, normalized to a cytosolic protein (the 20S proteasome subunit) to correct for cell damage by proteolysis, and compared with values in lysates of nonproteolysed explants (Fig. 3J). Although IL-1/20S proteasome ratios were similar in total lysates and protease-resistant fractions when explants were cultured in the presence of EP, thus faithfully reflecting intracellular IL-1, no detectable IL-1 was recovered after limited proteolysis of explants cultured without EP, despite comparable levels of the 20S proteasome reference. Taken together, this set of experimental evidence indicated that EP prevent IL-1 release from endometrial epithelial cells.
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release by purified epithelial cells
To directly address whether EP withdrawal induces IL-1 release, purified endometrial epithelial cells were adapted to culture with EP and then further cultured for 24 h with EP or after withdrawal of E, P, or both. Inhibitors of proteases were added to the medium to prevent degradation of released IL-1. Responses to hormonal modifications were consistent despite large variations between cultures in IL-1 mRNA and protein amounts (see range in legend to Fig. 4), which prompted us to normalize data to a reference condition. Complete or selective hormone withdrawal did not change IL-1 mRNA (Fig. 4A) or total (cells plus medium) IL-1 protein amounts (Fig. 4B). In striking contrast, removal of both E and P induced a major release of IL-1 from epithelial cells (13-fold increase; Fig. 4B). Either E or P was sufficient to prevent this release.
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production by epithelium-derived IL-1
We finally examined whether IL-1 released from epithelial cells was responsible for the induction of IL-1 expression by ESCs, initiating an amplification loop that would increase MMP production. First, purified ESCs were adapted for 8 d to culture with EP and then subjected for 24 h to withdrawal of E and/or P, with or without addition of recombinant IL-1 (Fig. 4C). Although EP withdrawal alone caused no significant change in IL-1 mRNA amounts, combination with IL-1 addition increased median IL-1 mRNA levels by 2.7-fold. A similar increase was observed when maintaining E but not P (alone or combined with E). To further determine whether epithelium-derived IL-1 could actually induce such IL-1 amplification, ESCs adapted in the presence of EP were further cultured for 24 h with medium conditioned by EP-deprived epithelial cells (containing 15 pg/ml IL-1). Just before addition to ESCs, this medium was supplemented or not with combined or separated E and P or with anti-IL-1 blocking antibody (Fig. 4, D and E). A median 4.7-fold increase in IL-1 mRNA levels was measured when the conditioned medium was not supplemented with EP (Fig. 4D). This increase was totally blocked by P alone but was not affected by E alone. Addition of anti-IL-1 blocking antibody prevented this response almost to the same extent as EP maintenance. These effects were paralleled by changes in MMP-1 expression (Fig. 4E): median MMP-1 mRNA levels in ESCs increased by 7-fold by omitting EP in the conditioned medium. This increase was abrogated by anti-IL-1 blocking antibody and inhibited to a large extent by P alone but not by E alone.
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Discussion |
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, IL-1β, and IL-1Ra, are well expressed in the cycling human endometrium, except IL-1β protein, which was below detection level in 40% of nonmenstrual endometria. Altogether, IL-1Ra is about 10-fold more abundant than IL-1 and IL-1β. Furthermore, IL-1Ra shows a 3- to 10-fold higher affinity for IL-1RI than IL-1 and IL-1β and efficiently blocks IL-1 activity in vitro (21). Hence, the system seems under tight control. However, up to 100- to 1000-fold excess of IL-1Ra is required to suppress the bioactivity of IL-1 agonists during disease (22). Thus, the local control of IL-1 activity by IL-1Ra remains to be clarified.
Although the three IL-1R ligands peak at menses, differences with the other phases and global effects of EP addition in explant cultures are modest as compared with other mediators of endometrium remodeling, such as LEFTY-A/Endometrial Bleeding-Associated Factor, or effectors such as MMP-1 and MMP-3 (3, 17). However, further discrimination of the two major cellular compartments by laser capture microdissection, which confirms preferential IL-1β expression by endometrial stroma compared with glands (23), evidences an ESC-specific control by EP for IL-1, but not for IL-1β or IL-1Ra expression. Preferential linear amplification of the 3'-end of mRNAs likely explains the approximately 100-fold lower mRNA levels detected in microdissected compartments compared with total extracts. In situ hybridization and immunolocalization further demonstrate that IL-1 expression in ESCs is repressed during the proliferative and secretory phases but induced at menses as well as in breaking-down areas during dysfunctional bleeding episodes. Thus, differential IL-1 expression in ESCs was masked in total tissue analyses, due to EP-insensitive IL-1 contribution by epithelial cells. To the best of our knowledge, a differential regulation of IL-1 expression in two major compartments of a given tissue has not been previously reported. Although IL-1 belongs to a family of cytokines produced by immune cells (21), it is essentially expressed by resident cells in the endometrium. Our data do not exclude that hematopoietic cells infiltrating the endometrium at the late secretory phase may release IL-1, but the abundant ESCs that produce IL-1 during menstruation and dysfunctional bleeding best overlap with labeling for a fibroblastic marker.
The second major finding is that IL-1 expression by ESCs is turned on by epithelial cell-derived IL-1 released upon EP withdrawal. This observation is fully compatible with, but calls for an elaboration of, our previous model of dual repression by EP of IL-1-mediated endometrial breakdown: EP blocking both IL-1 production and MMP-1 expression by IL-1-stimulated fibroblasts (6). Although in vivo demonstration is still required, we now further suggest that MMP-1 is actually under a triple control (Fig. 5). Before menstruation, EP protect tissue against proteolysis by blocking altogether epithelial IL-1 release, fibroblastic IL-1 expression, and MMP-1 production. Conversely, upon EP withdrawal, paracrine induction of stromal MMP-1 expression by epithelial-derived IL-1 is amplified through a paracrine and possibly autocrine stromal IL-1 loop (24, 25), resulting in rapid expansion of tissue breakdown at menstruation and dysfunctional bleeding episodes.
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synthesis by epithelial cells during nonmenstrual phases of the cycle is unclear, intracellular IL-1 accumulation during the secretory phase could provide a powerful and rapid mechanism to initiate menstrual response by preparing its release upon EP withdrawal, an effect amplified by an autocrine loop by ESCs. Release of preexisting IL-1 pools is rarely considered but was observed upon barrier disruption in murine epidermis (26). IL-1 release could result from apoptosis (27), which occurs in late secretory and menstrual endometrium, when ovarian steroids concentration decreases (28). Like in endometrium, skin epithelial cells (keratinocytes) constitutively express IL-1 (29). However, release is restricted to wound healing (30) and initiation of local inflammation (31). As for ESCs, IL-1 is not expressed in skin fibroblasts except during systemic sclerosis (32).
The mechanisms underlying differential regulation of IL-1 expression in epithelial and stromal cells are not clear yet. E and P regulate gene expression by cognate nuclear receptors, ERs and PRs, or through nongenomic mechanisms (33). Although variations of endometrial expression of the nuclear receptors along the menstrual cycle have been reported (34, 35), we could detect ER and PRs in glands and ESCs as well as in purified cells of both types, suggesting that these nuclear receptors are responsible for the hormonal control of IL-1 synthesis and/or release. Although withdrawal of both steroids was required for IL-1 release by epithelial cells, P, but not E, was sufficient to block the increase in IL-1 expression by ESCs due to recombinant IL-1 or induced by medium conditioned by epithelial cells. Subtle differences in the relative ratios of ER and PR isoforms could explain this differential response (34, 35, 36). Additional experiments addressing variations of stimulatory signals and IL-1 mRNA stability are necessary to clarify the underlying mechanisms (37). In conclusion, our data demonstrate that two populations of resident endometrial cells, epithelial and stromal cells, both play an important role in the production of IL-1 that triggers MMP-1 expression and tissue breakdown, not only at menses but also during dysfunctional bleeding episodes. Moreover, a paracrine amplification loop emerges as a potent mechanism to spread signaling leading to tissue breakdown. These data open new perspectives for therapies targeting IL-1 bioactivity, as illustrated by the successful use of recombinant IL-1Ra in rheumatoid arthritis (38). A better understanding of the mechanisms underlying differential IL-1 expression by epithelial and stromal cells and controlling its release deserves further attention.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: All authors have nothing to declare.
First Published Online July 15, 2008
1 E.M. and P.H. are equal senior authors. 
Abbreviations: E, Estradiol; ER, E receptor; ESC, endometrial stromal cell; IL-1Ra, IL-1 receptor antagonist; MMP, matrix metalloproteinase; P, progesterone; PR, P receptor.
Received November 28, 2007.
Accepted July 9, 2008.
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and tumor necrosis factor-. J Clin Endocrinol Metab 79:530–536[Abstract] and its dual block by ovarian steroids. Proc Natl Acad Sci USA 94:10341–10345 in human endometrial stromal cells. J Clin Endocrinol Metab 85:1611–1619 and tissue-lytic matrix metalloproteinase-1 are elevated in ectopic endometrium of patients with endometriosis. Hum Reprod 20:1695–1701 and basic fibroblast growth factor-mediated mechanisms. J Invest Dermatol 124:638–643[CrossRef][Medline] mediates collagenase synthesis stimulated by phorbol 12-myristate 13-acetate. J Biol Chem 269:11291–11298 expression and release from a pre-formed pool in murine epidermis. J Invest Dermatol 106:397–403[CrossRef][Medline] and -β mRNA. Keratinocyte epidermal cell-derived thymocyte-activating factor is identical to interleukin 1. J Exp Med 164:2095–2100 gene expression during wound healing. Wound Repair Regen 3:473–484[CrossRef][Medline] in basal epidermis. Proc Natl Acad Sci USA 92:11874–11878 gene expression and protein production by fibroblasts from patients with systemic sclerosis. Clin Exp Immunol 97:445–450[Medline] by a mechanism involving decreased stability of IL-1 mRNA. Mol Cell Endocrinol 155:123–133[CrossRef][Medline]This article has been cited by other articles:
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  H. P. Gaide Chevronnay, C. Galant, P. Lemoine, P. J. Courtoy, E. Marbaix, and P. Henriet Spatiotemporal Coupling of Focal Extracellular Matrix Degradation and Reconstruction in the Menstrual Human Endometrium Endocrinology, November 1, 2009; 150(11): 5094 - 5105. [Abstract] [Full Text] [PDF]
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C. Selvais, H. P. Gaide Chevronnay, P. Lemoine, S. Dedieu, P. Henriet, P. J. Courtoy, E. Marbaix, and H. Emonard Metalloproteinase-Dependent Shedding of Low-Density Lipoprotein Receptor-Related Protein-1 Ectodomain Decreases Endocytic Clearance of Endometrial Matrix Metalloproteinase-2 and -9 at Menstruation Endocrinology, August 1, 2009; 150(8): 3792 - 3799. [Abstract] [Full Text] [PDF]
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| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
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) of 1 nM E and 100 nM P (EP) (B, D, F, H, J, and L–O). A–L, Amounts of target mRNAs (A, B, E, F, I, and J) and proteins (C, D, G, H, K, and L) were measured in total lysates, normalized to β-actin mRNA and total proteins, respectively, and presented on logarithmic scales. Noncultured (NC) endometria [for mRNA and proteins: 35 and 24 from secretory phase (S); 15 and 11 from menstrual phase (M), and 28 and 19 from proliferative phase (P)] are presented as box plots showing 25th and 75th percentiles, medians (dots), and minimal and maximal values (vertical bars). For Kruskal-Wallis test: 
, P < 0.05, compared with condition with rhIL-1