The Transcription of Corticotropin-Releasing Hormone in Human Endometrial Cells Is Regulated by Cytokines

Makrigiannakis, Antonis; Margioris, Andreas; Zoumakis, Emmanouil; Stournaras, Christos; Gravanis, Achille

doi:10.1159/000054507

Cited by 43 publications

(33 citation statements)

References 45 publications

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“…Recently, a similar cross talk has been demonstrated in endometrial cells, where IL-6 induces CRH secretion by activating the CRH promoter (18), and in the adrenals, where CRH regulates IL-6 expression (30). In general, TNF-␣, IL-1␤, and IL-6 promote ACTH and glucocorticoid secretion, activating the stress system (14).…”

Section: Discussionmentioning

confidence: 67%

Corticotropin-Releasing Hormone Augments Proinflammatory Cytokine Production from Macrophages In Vitro and in Lipopolysaccharide-Induced Endotoxin Shock in Mice

Agelaki¹,

Tsatsanis²,

et al. 2002

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Corticotropin-releasing hormone (CRH) exerts an anti-inflammatory effect indirectly, via cortisole production, and a proinflammatory effect directly on immune cells. The aim of the present work was to examine the effect of CRH on macrophage-derived cytokines both in vitro and in vivo. For the in vitro experiments we used two types of macrophages: (i) the RAW264.7 monocyte/macrophage cell line and (ii) thioglycolate-elicited peritoneal macrophages from BALB/c mice. We have found that CRH enhanced lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and IL-6 production. For the in vivo experiments we have used the LPS-induced endotoxin shock model in BALB/c mice, an established model for systemic inflammation in which macrophages are the major source of the proinflammatory cytokines responsible for the development of the shock. Administration of antalarmin, a synthetic CRH receptor 1 (CRHR1) antagonist, prior to LPS prolonged survival in a statistically significant manner. The effect was more evident at the early stages of endotoxin shock. CRHR1 blockade suppressed LPS-induced elevation of the macrophagederived cytokines TNF-␣, IL-1␤, and IL-6, confirming the role of CRH signals in cytokine expression. In conclusion, our data suggest that CRH signals play an early and crucial role in augmenting LPS-induced proinflammatory cytokine production by macrophages. Our data suggest that the diffuse neuroendocrine system via CRH directly affects the immune system at the level of macrophage activation and cytokine production.Corticotropin-releasing hormone (CRH) affects the immune system. This effect can be indirect, via the end products of the two major axes of the adaptive response to stress, regulated by CRH, i.e., cortisole of the hypothalamus-pituitary-adrenals (HPA) axis and catecholamines of the sympathetic system (13). CRH also affects the immune system in a direct manner. Indeed, CRH is released at the site of inflammation by nerve terminals and epithelial cells, affecting resident immune cells (13,33). It should be noted that while the indirect effect of CRH is anti-inflammatory, its direct paracrine effect is definitely proinflammatory. Thus, blockade of its paracrine effect by specific anti-CRH serum attenuates the inflammatory response in several models of inflammation in vivo (15, 33). A major immune target of CRH is the mast cell (13, 25). However, in addition to mast cells a growing list of immune cells exhibits specific CRH binding sites. Thus, mouse splenocytes (34), human peripheral blood monocytes and lymphocytes (24), and monocytes/macrophages and Th cells (2) have CRH receptors. CRH receptors are also present in inflamed synovium (9) and inflamed subcutaneous tissues (19). CRHR1 expression is upregulated by lipopolysaccharide (LPS) stimulation (22). The aim of the present work was to study the effect of CRH on macrophages, the main source of the proinflammatory cytokines tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and IL-6, which initiate the in...

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Section: Discussionmentioning

confidence: 67%

Corticotropin-Releasing Hormone Augments Proinflammatory Cytokine Production from Macrophages In Vitro and in Lipopolysaccharide-Induced Endotoxin Shock in Mice

Agelaki¹,

Tsatsanis²,

et al. 2002

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“…The IL-1 receptor (type 1) (IL-1R t1) status of either cell line is not known and, if these cell lines are IL-1R t1 negative, an effect might not be seen. This latter explanation, however, seems unlikely as there are a number of reports of proteins being regulated by IL-1b in other endometrial epithelial carcinoma cell lines, such as RL952 and Ishikawa (Moghul et al 1994, Makrigiannakis et al 1999). In addition, there are similar reports of IL-1b regulating gene and protein expression in endometrial stromal cells (Huang et al 1998, Tsai et al 2001.…”

Section: Discussionmentioning

confidence: 99%

The effects of sex steroid hormones and interleukin-1-beta on MUC1 expression in endometrial epithelial cell lines

Horne¹,

Lalani²,

Margara³

et al. 2006

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Oestrogen, progesterone and paracrine signals from the embryo have been associated with the overall control of implantation. Changes in the expression of the heavily glycosylated transmembrane glycoprotein MUC1 mucin on the endometrial epithelium are also thought to be important for embryo attachment. Increased MUC1 expression has been correlated with elevated progesterone levels in the secretory phase of the menstrual cycle. Embryonic control of endometrial receptivity through changes in MUC1 expression could be achieved through the interleukin-1 system. Four endometrial epithelial cell lines (HEC1A, HEC1B, Ishikawa and RL592) were treated with oestrogen and progesterone (with or without interleukin-1-beta) and were subjected to immunocytochemistry and flow cytometric analysis to determine MUC1 production using MUC1 antibodies. HEC1A (oestrogen receptor (ER) and progesterone receptor (PR) positive) and HEC1B (ER positive and PR negative) were transfected with the MUC1 promoter, underwent similar treatment regimes and the activity of the MUC1 promoter relative to their untreated controls was determined using a chloramphenicol acetyltransferase (CAT) enzyme-linked immunoassay. Using the cell lines, we determined that endometrial MUC1 expression is up-regulated by progesterone, consistent with the in vivo increases in MUC1 related to high progesterone levels. We also revealed that neither oestrogen, nor interleukin-1-beta, appear to modulate MUC1. Progesterone-dependent regulation of MUC1 is likely to be an important factor in determining endometrial receptivity.

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“…Indeed, the inhibitory effect of the glucocorticoids in the endometrium is in agreement with that described for the hypothalamus and exactly opposite to what has been found to take place in human placenta, suggesting that the regulation of the transcription of the CRH gene is cell-specific depending on the presence or absence of certain specific transcription factors 49 . Finally, the cytokines IL-1 and IL-6 have been shown to stimulate the activity of the CRH promoter introduced in human endometrial cells 50 . This effect appears to be mediated via prostaglandins, in accordance to what has been described in the hypothalamus and placenta.…”

Section: Endometrial Crhmentioning

confidence: 99%

“…Regulation: It has been found that estrogens and the glucocorticoids suppress the secretion of endometrial b-endorphin while progesterone, dihydrotestosterone and the gonadal regulator GnRH do not significantly affect it 50 . Interestingly, the antiglucocorticoid-antiprogestin RU486 exhibits agonist effects, possibly acting via glucocorticoid receptors.…”

Section: Endometrial Opioid Peptidesmentioning

confidence: 99%

Stress neuropeptides in the human endometrium: Paracrine effects on cell differentiation and apoptosis

Gravanis¹,

Makrigiannakis²,

Chatzaki³

et al. 2002

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Human endometrium exhibits characteristics of a neuroendocrine-like stress organ in addition to its classical role as the main target of ovarian steroid hormones. Indeed, the epithelial cells of human endometrium express the stress-associated neuropeptide genes corticotropin-releasing hormone (CRH), proopiomelanocortin, proenkephalin and prodynorphin. Furthermore, endometrium stroma cells also express CRH when they differentiate into decidual cells. Multiple lines of evidence suggest that the stress-associated neuropeptides of human endometrium are under the endocrine control of gonadal steroids as well as under an autocrine/paracrine regulation by prostanoids and interleukins. Endometrial stress-associated neuropeptides appear to exert their biological effect locally, i.e. within the uterus since human endometrium and myometrium also express the relevant receptors. More specifically, recent data suggest that endometrial CRH participates in the regulation of intrauterine inflammatory processes taking place in early pregnancy including stroma decidualization, blastocyst implantation and early maternal tolerance. Similarly, endometrial opioids participate in the regulation of uterine tissue remodeling via their effect on endometrial cell apoptosis. Thus, endometrial stress neuropeptides act as paracrine regulators of uterine cell differentiation and tissue remodeling as well as modulators of local immune responses.

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The Transcription of Corticotropin-Releasing Hormone in Human Endometrial Cells Is Regulated by Cytokines

Cited by 43 publications

References 45 publications

Corticotropin-Releasing Hormone Augments Proinflammatory Cytokine Production from Macrophages In Vitro and in Lipopolysaccharide-Induced Endotoxin Shock in Mice

Corticotropin-Releasing Hormone Augments Proinflammatory Cytokine Production from Macrophages In Vitro and in Lipopolysaccharide-Induced Endotoxin Shock in Mice

The effects of sex steroid hormones and interleukin-1-beta on MUC1 expression in endometrial epithelial cell lines

Stress neuropeptides in the human endometrium: Paracrine effects on cell differentiation and apoptosis

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