Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The notion that stress activates central and peripheral pathways to inhibit the menstrual cycle is well accepted, but the initial processes through which this occurs have not been investigated. This study uses a relevant nonhuman primate model to document the cyclic endocrine effects imposed by a moderate short-term stress episode in the follicular phase. The stress paradigm is a 5-day inflammatory/immune-like challenge produced by the administration of bacterial endotoxin [lipopolysaccharide (LPS)], which, through the release of endogenous cytokines and other mediators, induces a physiopathological response similar to a bacterial infection. LPS was administered iv twice daily for 5 days starting on days 2-8 of the follicular phase. The stress challenge resulted in a significant lengthening of the follicular phase in all monkeys. Two distinct groups were observed. In group 1 (n = 5), the mean (+/- SE) length of the follicular phase in the LPS-treated cycle was significantly increased, from 10.2 +/- 0.2 in control cycle 2 to 30.8 +/- 4.3 days (except in one monkey that had a 4-month amenorrheic interval). In group 2 (n = 5), the length of the follicular phase significantly increased but not to exceed the duration of the LPS treatment (9.7 +/- 1.1 vs. 13.6 +/- 1.2). Estradiol concentrations decreased significantly after LPS in group 1 (34.8 +/- 5.5 vs. 16.2 +/- 6.5 pg/mL) and remained suppressed after the challenge. In group 2, estradiol levels remained stationary throughout the 5-day LPS treatment (26.0 +/- 6.5 vs. 25.6 +/- 3.9). Compared with control values at a similar stage of the follicular phase, most LH and FSH values during LPS treatment were higher than controls. Estradiol and gonadotropin surges were delayed by LPS treatment for a varying length of time according to each grp. Significant differences in integrated luteal progesterone concentrations characterized control cycles of groups 1 and 2 (group 1: 36.5 +/- 1.5, group 2: 47.5 +/- 2.6). In group 1, there were no further effects of LPS on luteal progesterone during the treatment and two post-LPS cycles. In contrast, in group 2, integrated luteal progesterone concentrations were significantly decreased in post-LPS cycle 1 (to 36.0 +/- 4.4). Cortisol significantly increased at hour 3 after each morning LPS injection but the amplitude of the response decreased over the 5-day period. Progesterone increased significantly by hour 3 after the first LPS injection but remained unchanged after subsequent LPS administration. Our data demonstrate that a 5-day inflammatory-like episode during the follicular phase can delay folliculogenesis and that damage to this process is intensified in individuals who already demonstrate a subtle cyclic degradation, in the form of decreased progesterone secretion in the luteal phases preceding the stress episode. Long-term endocrine effects, in the form of decreased luteal secretory activity in the first poststress cycle, are observed in normally cycling individuals, suggesting that inadequacy of the luteal phase may represent the first stage in the damage that a stress episode can inflict upon the normal menstrual cycle.
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PMID:Stress and the menstrual cycle: relevance of cycle quality in the short- and long-term response to a 5-day endotoxin challenge during the follicular phase in the rhesus monkey. 966 28

Previously, we reported that in the rhesus monkey a 5-day inflammatory-like stress during the early-mid follicular phase acutely stimulates the hypothalamic-pituitary-adrenal axis and exerts effects on the hypothalamic-pituitary-gonadal axis, delays folliculogenesis and in some animals decreases luteal function in the post-treatment cycle. Because the endocrine environment at the time of the stress may influence the response to the stress, we now investigate the acute and long-term responses to a similar stress challenge during the luteal phase of the menstrual cycle, at a time of progesterone dominance. Nine monkeys with normal cycles were injected with endotoxin (lipopolysaccharide; LPS, 150 microg i.v.) twice a day for 5 days starting on days 4-8 after the LH peak. Blood samples were taken at hour 3 and hour 8 after each morning LPS injection to monitor the acute gonadotropin and cortisol responses. To verify cyclicity, menses were checked every day, and daily blood samples were taken for estradiol and progesterone measurement. Two control cycles, the LPS treatment cycle, and two post-treatment cycles were documented. Endotoxin activated the adrenal axis: mean (+/-SE) cortisol secretion was significantly increased at hour 3 after the first morning LPS injection (74.1 +/- 4.9 vs. 24.1 +/- 1.8 microg/dL in the control; P < 0.05) and remained elevated at hour 8. This response decreased progressively with time: on day 5 of LPS treatment, the cortisol level was still significantly higher than control at hour 3 (38.5 +/- 5.0 microg/dL; P < 0.05) but had returned to the control concentration by hour 8 (days 3-5 of LPS). Mean integrated progesterone through the luteal phase of the LPS treatment cycle was significantly decreased (33.5 +/- 3.3 ng/ml vs. 48.9 +/- 3.7 and 54.0 +/- 4.9 in the two control cycles; P < 0.05), but luteal phase length remained unchanged. When compared with control levels on the same day of the luteal phase, about one third of LH and FSH values were lower than one SD below mean control levels. LPS administration had no effect on the two post-treatment cycles, except that integrated luteal progesterone in 3 out of 9 monkeys was still reduced in post-treatment cycle 1. There were no differences in follicular phase length and preovulatory estradiol peaks between control cycles and post-treatment cycles. When compared with our previous study, the results illustrate specific responses to stress at different phases of the menstrual cycle and support the notion that a moderate short-term inflammatory-like stress episode has the potential to subtly alter critical aspects of cyclicity.
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PMID:Stress and the menstrual cycle: short- and long-term response to a five-day endotoxin challenge during the luteal phase in the rhesus monkey. 1002 27

In the present study we examined the involvement of interleukin (IL)-1alpha, -1beta, FSH, and lipopolysaccharide (LPS) in the regulation of IL-1alpha and -1beta production by Sertoli cells under in vitro conditions. Sertoli cell cultures from immature mice produced constitutively basal levels of intracellular IL-1alpha. Stimulation of Sertoli cell cultures with LPS (5 microgram/ml) resulted in a maximal production of intracellular IL-1alpha 2 h after the stimulation. Thereafter, these levels decreased but remained significantly higher within 24 h after stimulation than those in control cultures. The effect of LPS on IL-1alpha production was dose dependent. FSH did not show any effect on intracellular IL-1alpha production by Sertoli cells. IL-1alpha could not be detected in supernatants of unstimulated or stimulated Sertoli cell cultures. Sertoli cell cultures stimulated with recombinant IL-1alpha induced optimal intracellular levels of IL-1alpha within 2 h of stimulation. These levels remained high 24 h after stimulation. However, stimulation of Sertoli cell cultures with IL-1beta induced a peak of IL-1alpha production 8 h after stimulation. These levels decreased 24 h after the stimulation but were still found to be significantly higher than those in control cultures. The addition of IL-1 receptor antagonist (IL-1ra) to Sertoli cell cultures did not significantly alter their capacity to produce IL-1alpha. However, the stimulatory effects of recombinant IL-1alpha on IL-1alpha production by Sertoli cell cultures were reversed by the concomitant addition of recombinant IL-1ra. No immunoreactive IL-1beta could be detected in lysates or conditioned media of immature murine Sertoli cells under any of the stimulatory conditions outlined. Our results may suggest the involvement of physiological (IL-1) and pathophysiological factors (LPS) in the regulation of spermatogenesis and spermiogenesis processes and male fertility.
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PMID:Induction of interleukin-1alpha production in murine Sertoli cells by interleukin-1. 1077 79

In adult rats, bacterial endotoxin (lipopolysaccharide or LPS) is known to diminish the activity of the reproductive axis, mainly by inhibiting luteinizing hormone-releasing hormone (LHRH) secretion; until now, this effect has not been studied in immature rats. The aim of the present study was to evaluate the effect of LPS 1) on LHRH output (and associated changes in the release of inhibitory amino acid neurotransmitters such as gamma-aminobutyric acid (GABA) and taurine) by superfused hypothalamic fragments, and 2) on gonadotropin secretion by incubated hemipituitaries, obtained from young adult (60-day-old) and peripubertal (30-day-old) intact male rats. In adult animals, LPS induced a significant inhibition (50% of basal values) of LHRH release, accompanied by an increase in GABA and taurine output. In juvenile rats the inhibition of LHRH secretion by LPS attained 90% of basal values (p<0.0001 versus adult rats), and the concurrent increase in GABA release was significantly greater (p<0.0001 versus adult rats). LPS did not affect in vitro gonadotropin secretion in adult animals. Conversely, the release of these hormones was significantly (p<0.001 and <0.02 for LH and FSH, respectively) reduced in 30-day-old rats. Our results demonstrate the existence of age-related differences in the effect of LPS on LHRH and gonadotropin secretion. These differences might well be attributed to an increased activity of the hypothalamic GABAergic system. Furthermore, the participation of other factors known to play a role in immune-neuroendocrine relationships (e.g., corticotropin-releasing hormone, testosterone) is discussed.
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PMID:Age-related differences in the effects of bacterial endotoxin (LPS) upon the release of LHRH, gonadotropins and hypothalamic inhibitory amino acid neurotransmitters measured in tissues explanted from intact male rats. 1092 20

Folliculostellate cells of the anterior pituitary are postulated to be an important source of factors, such as follistatin, that regulate pituitary function by intercellular communication. To gain further insight into the function of this cell type, folliculostellate cells were enriched from cultured rat anterior pituitary cells, and an immortalized cell line designated FS/D1h was established and characterized. These FS/D1h cells express S100 immunoreactivity and produce IL-6 but not pituitary hormones such as GH, ACTH, FSH, and LH. Importantly, FS/D1h cells express large amounts of follistatin mRNA and secrete the protein, as quantified indirectly by the amount of [(125)I]activin A immunoprecipitated with a follistatin antiserum. The FS/D1h cells also express alpha, betaA, and betaB inhibin/activin subunit mRNAs, but whether they produce the corresponding activins and inhibins has not been determined. The response of FS/D1h cells to agents thought to modulate folliculostellate cell function was evaluated. IL-1beta (0.005-5 nM) stimulated the secretion of follistatin and increased mRNA expression. In parallel, IL-6 secretion was stimulated. Dexamethasone, pituitary adenylate cyclase-activating polypeptide(1-27), and lipopolysaccharide but not testosterone, 12-O-tetradecanoylphorbol-13-acetate, or forskolin also increased follistatin secretion. Surprisingly, activin had no effect on follistatin mRNA levels, despite the fact that FS/D1h cells express ActRII, ActRIIB, and ALK-4 (ActRIB). Activin, on the other hand, induced Smad7 mRNA accumulation and exerted an antiproliferative effect on FS/D1h cells. Altogether, these observations support the possibility that follistatin originating from folliculostellate cells participates in mediating the effects of IL-1beta, glucocorticoids, and other agents on the response of pituitary cells to activins.
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PMID:Rat anterior pituitary folliculostellate cells are targets of interleukin-1beta and a major source of intrapituitary follistatin. 1253 36

Sertoli cells play a key role in testicular function and their final number in the adult testis determines the capacity of germ cell production. Sertoli cell proliferation, stimulated by FSH and paracrine factors, occurs only in fetal and prepubertal life and may be an important target of pathogenic influences affecting testis development. We used a Sertoli cell proliferation assay to address the question whether if bacterial endotoxin (lipopolysaccharide; LPS) and proinflammatory cytokines could influence early postnatal Sertoli cell development. LPS and tumor necrosis factor-alpha (TNF-alpha) dose-dependently stimulated proliferation of primary cultures of isolated Sertoli cells from 8- to 9-day-old rats, assessed by (3)H-thymidine and BrdU incorporation. LPS also significantly increased the number of living cells in culture, measured by supravital staining. Interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) had no direct effect on Sertoli cell growth, but were found to modulate FSH action. IL-6 increased, while IFN-gamma inhibited, FSH-induced Sertoli cell DNA-synthesis. We conclude that endotoxin and TNF-alpha are potent direct stimulators of Sertoli cell proliferation in vitro, and that IL-6 and IFN-gamma can modulate the mitogenic action of FSH on immature Sertoli cells. This may contribute to the pathogenesis of testicular damage after infections and inflammatory diseases in fetal and early postnatal life, with subsequent disturbance of adult germ cell production.
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PMID:Endotoxin and proinflammatory cytokines modulate Sertoli cell proliferation in vitro. 1502 75

IL-1 is well known to be involved in the immune system and have a role in ovarian inflammation as well as exhibiting inhibitory effects on steroidogenesis and folliculogenesis. Because multiple aspects of ovarian function have also been shown to involve cytokine/chemokine networks, IL-1alpha-induced chemokine gene expression in mouse granulosa cells was investigated. Granulosa cells from immature mice at 28 d of age were cultured with IL-1alpha (10 ng/ml). IL-1alpha induced abundantly and specifically keratinocyte chemoattractant (KC) chemokine, a CXC subfamily. KC chemokine mRNA and protein were increased 1-2 h after IL-1alpha and then gradually decreased. The KC promoter (-701/+30) containing three nuclear factor (NF)-kappaB sites was fully responsive to IL-1alpha, whereas deletions and mutants of the NF-kappaB sites lowered the responsiveness to IL-1alpha. The proximal NF-kappaB site (-69/-59) played a critical role in regulating IL-1alpha-induced KC chemokine promoter activity. Overexpression of the inhibitor of NF-kappaB (IkappaB) blocked KC promoter activity induced by IL-1alpha, whereas overexpression of p65, a component of NF-kappaB, increased promoter activity and mRNA of KC chemokine. In addition, FSH did not affect NF-kappaB signaling or IL-1alpha-induced KC chemokine promoter activity. Within 1-3 h after ip injection of lipopolysaccharide (100 mug/mouse), a product known to stimulate release of IL-1, KC chemokine was localized in the ovary to granulosa cells as well as the thecal-interstitial layer. The results of this study indicate that KC gene is a chemokine induced acutely by IL-1alpha via NF-kappaB signaling in mouse granulosa cells.
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PMID:Interleukin-1alpha-induced chemokines in mouse granulosa cells: impact on keratinocyte chemoattractant chemokine, a CXC subfamily. 1682 93

Oestrogens are pivotal in ovarian follicular growth, development and function, with fundamental roles in steroidogenesis, nurturing the oocyte and ovulation. Infections with bacteria such as Escherichia coli cause infertility in mammals at least in part by perturbing ovarian follicle function, characterised by suppression of oestradiol production. Ovarian follicle granulosa cells produce oestradiol by aromatisation of androstenedione from the theca cells, under the regulation of gonadotrophins such as FSH. Many of the effects of E. coli are mediated by its surface molecule lipopolysaccharide (LPS) binding to the Toll-like receptor-4 (TLR4), CD14, MD-2 receptor complex on immune cells, but immune cells are not present inside ovarian follicles. The present study tested the hypothesis that granulosa cells express the TLR4 complex and LPS directly perturbs their secretion of oestradiol. Granulosa cells from recruited or dominant follicles are exposed to LPS in vivo and when they were cultured in the absence of immune cell contamination in vitro they produced less oestradiol when challenged with LPS, although theca cell androstenedione production was unchanged. The suppression of oestradiol production by LPS was associated with down-regulation of transcripts for aromatase in granulosa cells, and did not affect cell survival. Furthermore, these cells expressed TLR4, CD14 and MD-2 transcripts throughout the key stages of follicle growth and development. It appears that granulosa cells have an immune capability to detect bacterial infection, which perturbs follicle steroidogenesis, and this is a likely mechanism by which ovarian follicle growth and function is perturbed during bacterial infection.
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PMID:Ovarian follicular cells have innate immune capabilities that modulate their endocrine function. 1796 59

Infections of the reproductive tract or mammary gland with Gram-negative bacteria perturb ovarian function, follicular growth, and fecundity in cattle. We hypothesized that lipopolysaccharide (LPS) from Gram-negative bacteria stimulates an inflammatory response by ovarian granulosa cells that is mediated by Toll-like receptor (TLR) 4. The present study tested the capacity of bovine ovarian granulosa cells to initiate an inflammatory response to pathogen-associated molecular patterns and determined subsequent effects on the in vitro maturation of oocytes. Granulosa cells elicited an inflammatory response to pathogen-associated molecular patterns (LPS, lipoteichoic acid, peptidoglycan, or Pam3CSK4) with accumulation of the cytokine IL-6, and the chemokine IL-8, in a time- and dose-dependent manner. Granulosa cells responded acutely to LPS with rapid phosphorylation of TLR signaling components, p38 and ERK, and increased expression of IL6 and IL8 mRNA, although nuclear translocation of p65 was not evident. Targeting TLR4 with small interfering RNA attenuated granulosa cell accumulation of IL-6 in response to LPS. Endocrine function of granulosa cells is regulated by FSH, but here, FSH also enhanced responsiveness to LPS, increasing IL-6 and IL-8 accumulation. Furthermore, LPS stimulated IL-6 secretion and expansion by cumulus-oocyte complexes and increased rates of meiotic arrest and germinal vesicle breakdown failure. In conclusion, bovine granulosa cells initiate an innate immune response to LPS via the TLR4 pathway, leading to inflammation and to perturbation of meiotic competence.
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PMID:Lipopolysaccharide initiates inflammation in bovine granulosa cells via the TLR4 pathway and perturbs oocyte meiotic progression in vitro. 2199 Mar 8

Neonatal lipopolysaccharide (LPS) exposure alters neuroendocrine, immune and behavioural responses in adult rats. Recent findings indicate that neonatal LPS treatment may have a more pronounced effect on the mating behaviours of females compared to males. The current study further explored the impact of neonatal inflammation on reproductive development in the female rat. Wistar rats were administered LPS (0.05 mg/kg, i.p.) or saline (equivolume) on postnatal days (PNDs) 3 and 5. The immediate effect of treatment was assessed on plasma corticosterone and tyrosine hydroxylase (TH) phosphorylation in the adrenal medulla. Weight gain and vaginal opening were recorded, and oestrous cyclicity was monitored post-puberty and in late adulthood. Blood and ovaries were collected throughout development to assess HPA and HPG hormones and to examine ovarian morphology. Reproductive success in the first (F1) generation and reproductive development in the second (F2) generation were also assessed. Neonatal LPS exposure resulted in increased TH phosphorylation in the neonatal adrenals. LPS treatment increased the corticosterone concentrations of females as juveniles, adolescents and adults, and reduced FSH in adolescence. Increased catch-up growth was evident in LPS-treated females, prompting earlier onset of puberty. Diminished follicular reserve was observed in neonatally LPS-treated females along with the advanced reproductive senescence. While fertility rates were not compromised, higher mortality and morbidity were observed in litters born to LPS-treated mothers. Female offspring of LPS-treated mothers displayed increased corticosterone on PND 14, increased catch-up growth and delayed emergence of the first oestrous cycle. No differences in any of the parameters assessed were observed in F2 males. These data suggest that neonatal immunological challenge has a profound impact on the female reproductive development, via the alteration of metabolic and neuroendocrine factors which regulate sexual maturation. Evidence of altered development in the female, but not male offspring of LPS-treated dams suggests increased susceptibility of females to the deleterious effects of neonatal immunological stress and its possible transferability to a subsequent generation.
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PMID:Neonatal immune challenge alters reproductive development in the female rat. 2236 7


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