Cytokine regulation of metalloproteinase gene expression

Matrix metalloproteinases belong to a family of zinc-dependent enzymes capable of degrading extracellular matrix and basement membrane components. Their expression is greatly modulated by cytokines and growth factors and involves the gene products of the Fos and Jun families of oncogenes. After extra(peri)cellular activation, their activity can be further controlled by specific tissue inhibitors of metalloproteinases. A correct balance between these regulatory mechanisms is necessary to ensure matrix remodeling in normal physiological processes such as embryonic development, but the overexpression of these enzymes may initiate or contribute to pathological situations such as cartilage degradation in rheumatoid arthritis or to tumor progression and metastasis. Delineation of the mechanisms of metalloproteinase and metalloproteinase inhibitors gene expression, understanding of their mode of interactions, and characterization of their patterns of expression in various tissues in normal and pathological states will lead to new therapeutic strategies to counteract the deleterious effects of matrix metalloproteinases in human disease.     

Cytokine regulation of IL-1 beta gene expression in the human polymorphonuclear leukocyte

Although recently polymorphonuclear leukocytes (PMN) have been identified as producers of IL-1 beta in response to LPS and granulocyte/monocyte colony stimulating factor, little is known regarding the ability of other cytokines to induce the production of IL-1 beta in the PMN. Inasmuch as IL-1 and TNF have been shown to be important priming agents, as well as agents that induce migration of PMN, we investigated their effect on IL-1 beta gene expression in human peripheral blood PMN. In the present study, we demonstrate that human peripheral blood PMN produce IL-1 beta in response to IL-1 alpha, IL-1 beta, and TNF-alpha. Control (unstimulated) human PMN had virtually undetectable levels of IL-1 beta mRNA. Either IL-1 beta or TNF, induced PMN to transiently express IL-1 beta mRNA with peak expression at 1 h, returning to untreated levels by 2 h. A dose response indicated that as little as 0.05 ng/ml of IL-1 beta or TNF resulted in IL-1 beta induction, with maximal effects at 1 ng/ml of IL-1 beta and 5 ng/ml of TNF. IL-1 alpha or IL-1 beta exhibited similar dose responses in IL-1 beta mRNA induction. Inasmuch as cytokines have been shown to have synergistic effects in cell function studies, we induced PMN with a combination of maximally effective doses of TNF plus IL-1 beta. They demonstrated a cooperative effect on IL-1 beta gene expression, in that mRNA levels were sustained for three hours. IL-1 beta Ag expression, as measured by ELISA, paralleled IL-1 beta mRNA expression with cell associated peak levels at 2 to 4 h. IL-1 beta Ag levels in PMN lysates and supernatants correlated with IL-1 beta mRNA levels, i.e., TNF + IL-1 greater than TNF greater than IL-1. Thus, these studies represent the first demonstration of IL-1 and TNF induction of IL-1 beta gene expression in the PMN. Furthermore, the time course of induction is unique to the PMN, with peak induction of mRNA at 1 h, which is consistent with the short lived nature of these cells in inflammatory lesions.     

Hormonal regulation of MUC1 expression.

Several circulating mucinous markers, including CA 15.3, MCA, CA 459, CASA, and Truquant BR, are secreted products of the polymorphic MUC1 gene, and are used as diagnostic tools in patients with breast cancer. In clinical practice the measurement of the levels of these markers in the blood can give important information on the tumor's response to treatment and its biological behavior during disease monitoring. Since the marker levels reflect the activity of the tumor, it is important to know all factors influencing the production/secretion and the blood concentrations of MUC1 mucin. Recent findings suggest that MUC1 gene expression is regulated by steroid hormones and other substances present in the serum. Such observations are very important not only because of their biological significance but also for their clinical implications, as one approach to breast cancer therapy is based on chemical hormone manipulation. Nevertheless, we have preliminarily demonstrated that endocrine treatment in breast cancer patients does not influence the circulating CA 15.3 serum levels, so changes in marker levels are related only to the clinical evolution of the tumor.     

促性腺激素释放激素受体及其基因表达调控

促性腺激素释放激素（ＧｎＲＨ,ＬＨＲＨ）在体内的重要功能是由ＧｎＲＨ受体介导的。ＧｎＲＨ受体是近年神经分内分泌和生殖生物学研究的热点之一,本文从ＧｎＲＨ受体的分子结构,ＧｎＲＨ受体基因表达调控,ＧｎＲＨ受体分布及表达,调节ＲｎＲＨ受体的因素以及ＧｎＲＨ受体介导的细胞信号转导等几个方面对ＧｎＲＨ受体近年来的研究进展进行了综述,对ＧｎＲＨ受体的研究,将有助于人们进一步了解ＧｎＲＨ受体在生殖调节和恶性肿     

Differential gene expression and regulation of type-1 angiotensin II receptor subtypes in the rat.

A simplified and sensitive method for measuring expression levels of type-1 angiotensin II (AT1) receptor subtypes, AT1A and AT1B, was established. The two receptor cDNAs were co-amplified and measured by polymerase chain reaction using primers based on the corresponding receptor subtype genes. Both AT1A and AT1B mRNAs were widely expressed in the rat tissues including adrenal gland, kidney, heart, aorta, lung, liver, testis, pituitary gland, cerebrum and cerebellum. AT1A mRNA was predominantly expressed in the rat tissues examined except adrenal gland and pituitary gland where AT1B mRNA was predominantly expressed. Sodium depletion did not change mRNA levels of AT1A and AT1B in the all tissues. However, both AT1A and AT1B mRNA levels in the heart and aorta were down-regulated by treatment with AT1 specific antagonist, TCV 116. In contrast, AT1B mRNA in the adrenal gland was mainly reduced by the treatment. These results suggest that the expression level of AT1B mRNA in the adrenal gland depends on the activity of the renin-angiotensin-aldosterone system (RAAS) and both receptor subtypes mediate contraction and hypertrophy of the smooth and cardiac muscles via the RAAS.     

Differential regulation of neuregulin 1 expression by progesterone in astrocytes and neurons

Glial-neuronal interactions are crucial processes in neuromodulation and synaptic plasticity. The neuregulin 1 family of growth and differentiation factors have been implicated as bidirectional signaling molecules that are involved in mediating some of these interactions. We have shown previously that neuregulin 1 expression is regulated by the gonadal hormones progesterone and 17beta-estradiol in the CNS, which might represent a novel, indirect mechanism of the neuromodulatory actions of these gonadal hormones. In the present study, we sought to determine the effects of progesterone and 17beta-estradiol on neuregulin 1 expression in rat cortical astrocytes and neurons in vitro. We observed that progesterone increased the expression of neuregulin 1 mRNA and protein in a dose-dependent manner in cultured astrocytes, which was blocked by the progesterone receptor antagonist RU-486. In contrast, 17beta-estradiol did not increase either neuregulin 1 mRNA or protein in astrocytes. We observed no effect of either progesterone or 17beta-estradiol on neuregulin 1 mRNA and protein in rat cortical neurons in vitro. Finally, we observed that treatment of cortical neurons with recombinant NRG1-beta1 caused PSD-95 to localize in puncta similar to that observed following treatment with astrocyte-conditioned medium. These results demonstrate that progesterone regulates neuregulin 1 expression, principally in astrocytes. This might represent a novel mechanism of progesterone-mediated modulation of neurotransmission through the regulation of astrocyte-derived neuregulin 1.     

Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus

The objective of this study was to determine whether uterine stromal and/or epithelial progesterone receptor (PR) is required for the antagonism by progesterone (P(4)) of estradiol-17beta (E(2)) action on expression of PR and lactoferrin in uterine epithelium. Uterine tissue recombinants were prepared with epithelium (E) and stroma (S) from wild-type (wt) and PR knockout (PRKO) mice: wt-S+wt-E and PRKO-S+wt-E. P(4) action on epithelial PR expression was studied in wt-S+wt-E and PRKO-S+wt-E tissue recombinants. E(2) down-regulated epithelial PR in both types of tissue recombinants, but P(4) blocked E(2)-induced down-regulation of epithelial PR only in wt-S+wt-E tissue recombinants. Thus, P(4) requires stromal PR to inhibit E(2)-induced down-regulation of epithelial PR. Epithelial PR is not sufficient in itself. The inhibitory effect of P(4) on lactoferrin expression was studied in 4 types of tissue recombinants (wt-S+wt-E, PRKO-S+wt-E, wt-S+PRKO-E, and PRKO-S+PRKO-E). E(2) induced lactoferrin in all 4 types of tissue recombinants. P(4) blocked E(2)-induced lactoferrin expression only in wt-S+wt-E tissue recombinants. In wt-S+PRKO-E tissue recombinants, P(4) inhibited lactoferrin expression only partially. P(4) failed to block E(2)-induced lactoferrin expression in PRKO-S+wt-E and PRKO-S+PRKO-E tissue recombinants. Thus, both epithelial and stromal PR are essential for full P(4) inhibition of E(2)-induced lactoferrin expression.     

Differentiation of murine embryonic stem cells induces progesterone receptor gene expression

The role of steroid hormone receptors in very early embryonic development remains unknown. Clearly, expression during organogenesis is important for tissue-specific development. However, progesterone receptor (PR) and estrogen receptors (ERalpha, ERbeta) are expressed during early development through the blastocyst stage in mice and other species, and yet are not essential for embryonic viability. We have utilized the mouse embryonic stem (mES) cell model to investigate the regulated expression of these receptors during differentiation. Surprisingly, one of the earliest changes in gene expression in response to a differentiation signal observed is PR gene induction. It parallels the time course of expression for the patterning genes Hoxb1 and Hoxa5. Unexpectedly, PR gene expression is not regulated in an estrogen-dependent manner by endogenous ERs or by transiently overexpressed ERalpha. Our results suggest a potentially novel mechanism of PR gene regulation within mES cells compared to adult tissues and the possibility of unique targets of PR action during early mES cell differentiation.     

Membrane progesterone receptor expression in mammalian tissues: A review of regulation and physiological implications

The recent discovery of a novel, membrane localized progestin receptor (mPR) unrelated to the classical progesterone receptor (PR) in fishes and its subsequent identification in mammals suggests a potential mediator of non-traditional progestin actions, particularly in tissues where PR is absent. While early studies on mPR focused on final oocyte maturation in fishes, more current studies have examined mPRs in multiple mammalian systems in both reproductive and non-reproductive tissues as well as in diseased tissues. Here we review the current data on mPR in mammalian systems including male and female reproductive tracts, liver, neuroendocrine tissues, the immune system and breast and ovarian cancer. We also provide new data demonstrating mPR expression in the RAW 264.7 immune cell line and bone marrow-derived macrophages as well as mPR expression and downstream gene regulation in ovarian cancer cells.