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Steroid inhibition of calcitriol-induced prolactin production in GH4C1 cells. Specificity and sensitivity.

ABSTRACT: The induction of prolactin (PRL)-gene expression by calcitriol (1,25-dihydroxyvitamin D3, 1,25-dihydroxycholecalciferol) in clonal rat pituitary tumour (GH4C1) cells was selectively inhibited by cortisol [IC50 (concentration causing 50% inhibition) = 3.2-4.1 nM]. The steroid specificity of this effect was investigated and various steroids were found to inhibit calcitriol-stimulated PRL production with the following relative potencies: cortisol, 1; dexamethasone, 8; 11-deoxycortisol, 0.5; corticosterone, 0.4; aldosterone, 0.07; testosterone and oestradiol, less than 0.003. The steroid antagonist RU 38486 did not affect basal or calcitriol-stimulated PRL production, but antagonized the effect of 10 nM-cortisol in a concentration-dependent manner. Neither progesterone nor 11-deoxycortisol antagonized the effect of 10 nM-cortisol. Calcitriol-induced PRL production was 14 times more sensitive to dexamethasone inhibition than was non-stimulated PRL production. Growth-hormone production was stimulated by dexamethasone, in the presence or absence of calcitriol, with a concentration-dependence similar to that of dexamethasone inhibition of basal PRL production. These data indicate that steroid inhibition of calcitriol-stimulated PRL production is a specific glucocorticoid effect. The sensitivity of calcitriol-stimulated PRL production to dexamethasone was 14-26-fold greater than that of other measured responses in the same cells. Two of the possible explanations for this selectively increased sensitivity to glucocorticoids are: amplification of the glucocorticoid effect via an induced mediator; and the presence of very-high-affinity glucocorticoid-receptor-binding sites on DNA.

SUBMITTER: Wark JD

PROVIDER: S-EPMC1147573 | biostudies-other | 1987 Jan

REPOSITORIES: biostudies-other

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Project description:Application of allergens onto the sublingual epithelium is used to desensitize allergic individuals, a treatment known as sublingual immunotherapy. However, the response of sublingual epithelial cells to house dust mite allergen and potential tolerance-promoting adjuvants such as Toll-like receptor (TLR) ligands and calcitriol has not been investigated. In order to study this, primary sublingual epithelial cells were isolated from dogs and cultured in vitro. After 24-h incubation with a Dermatophagoides farinae extract, a Dermatophagoides pteronyssinus extract, TLR2 ligands (FSL-1, heat-killed Listeria monocytogenes, Pam3CSK4), a TLR3 ligand (poly I:C), a TLR4 ligand [lipopolysaccharide (LPS)], and calcitriol (1,25-dihydroxyvitamin D3), viability of the cells was analyzed using an MTT test, and their secretion of interleukin 6 (IL-6), IL-10, CXCL8, and transforming growth factor β1 (TGF-β1) was measured by enzyme-linked immunosorbent assay. Additionally, to evaluate its potential effect as an adjuvant, sublingual epithelial cells were incubated with calcitriol in combination with a D. farinae extract followed by measurement of CXCL8 secretion. Furthermore, the effect of D. farinae and calcitriol on the transcriptome was assessed by RNA sequencing. The viability of the sublingual epithelial cells was significantly decreased by poly I:C, but not by the other stimuli. CXCL8 secretion was significantly increased by D. farinae extract and all TLR ligands apart from LPS. Calcitriol significantly decreased CXCL8 secretion, and coadministration with D. farinae extract reduced CXCL8 concentrations to levels seen in unstimulated sublingual epithelial cells. Although detectable, TGF-β1 secretion could not be modulated by any of the stimuli. Interleukin 6 and IL-10 could not be detected at the protein or at the mRNA level. It can be concluded that a D. farinae extract and TLR ligands augment the secretion of the proinflammatory chemokine CXCL8, which might interfere with sublingual desensitization. On the other hand, CXCL8 secretion was reduced by coapplication of calcitriol and a D. farinae extract. Calcitriol therefore seems to be a suitable candidate to be used as adjuvant during sublingual immunotherapy.

Project description:PurposeMenstrual cycle characteristics are markers of endocrine milieu. However, associations between age at menarche and adulthood sex steroid hormone levels have been inconsistent, and data on menstrual characteristics and non-sex steroid hormones are sparse.MethodsWe assessed the relations of menstrual characteristics with premenopausal plasma sex steroid hormones, sex hormone binding globulin (SHBG), prolactin, and growth factors among 2,745 premenopausal women (age 32-52) from the Nurses' Health Study II. Geometric means and tests for trend were calculated using multivariable general linear models.ResultsEarly age at menarche was associated with higher premenopausal early-follicular free estradiol (percent difference < 12 vs. > 13 years = 11%), early-follicular estrone (7%), luteal estrone (7%), and free testosterone (8%) (all p trend < 0.05). Short menstrual cycle length at age 18-22 was associated with higher early-follicular total (< 26 vs. > 39 days = 18%) and free estradiol (16%), early-follicular estrone (9%), SHBG (7%), lower luteal free estradiol (- 14%), total (- 6%), and free testosterone (- 15%) (all p trend < 0.05). Short adult menstrual length was associated with higher early-follicular total estradiol (< 26 vs. > 31 days = 14%), SHBG (10%), lower luteal estrone (- 8%), progesterone (- 9%), total (- 11%) and free testosterone (- 25%), and androstenedione (- 14%) (all p trend < 0.05). Irregularity of menses at 18-22 was associated with lower early-follicular total (irregular vs. very regular = - 14%) and free estradiol (- 14%), and early-follicular estrone (- 8%) (All p trend < 0.05). Irregularity of adult menstrual cycle was associated with lower luteal total estradiol (irregular vs. very regular = - 8%), SHBG (- 3%), higher total (8%), and free testosterone (11%) (all p trend < 0.05).ConclusionsEarly-life and adulthood menstrual characteristics are moderately associated with mid-to-late reproductive year's hormone concentrations. These relations of menstrual characteristics with endogenous hormone levels could partially account for associations between menstrual characteristics and reproductive cancers or other chronic diseases.

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Steroid inhibition of calcitriol-induced prolactin production in GH4C1 cells. Specificity and sensitivity.

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