The Auto/paracrine regulation of endocrine functions: a history of TGF-β and the adrenal cortex

Aquesta breu revisió vol analitzar quinze anys de recerca que han portat a proposar el factor de creixement transformant beta (TGF-β) com un component endogen auto/paracrí de la regulació de les funcions diferenciades de teixits endocrins, com el còrtex adrenal. El TGF-β reuneix els criteris requerits per aquesta funció, és a dir: a) El pèptid TGF-β està produït per les cèll. ules adrenocorticals i expressat in situ en aquest teixit; b) el TGF-β reprimeix considerablement la capacitat esteroidogènica d'aquestes cèll. ules reprimint els marcadors clau de diferenciació; c) l'hormona sistèmica ACTH modula la resposta de les cèll. ules adrenocorticals al TGF-β; d) la supressió de la síntesi de TGF-β suprimeix la inhibició de l'activitat esteroidogènica d'aquestes cèll. ules. El sistema del TGF-β adrenocortical és, al nostre entendre, el primer circuit regulador (loop) clarament establert en un teixit endocrí. Aquest viatge històric és un tribut al nostre amic José Sáez, que va participar activament en el coneixement d'aquesta història.This brief review is intended as a flash-back spanning over fifteen years of research and finally leading to the proposal that TGF-β could be an endogenous, auto/paracrine component in the regulation of the differentiated functions of an endocrine tissue, i.e., the adrenal cortex. TGF-β meets the criteria required for such a function: (i) the peptide is produced by adrenocortical cells and expressed in the tissue in situ; (ii) TGF-β strikingly down-regulates the steroidogenic capacity of these cells by repressing key differentiation markers; (iii) the systemic hormone ACTH modulates the adrenocortical cells’ responsiveness to TGF-β, and (iv) the suppression of TGF-β synthesis releases the inhibition of the steroidogenic activity of these cells. The TGF-β adrenocortical cell system was, to our knowledge, the first autocrine regulatory loop clearly established in an endocrine tissue. This chronological account is a tribute to our friend, José Sáez, who actively contributed to this history

IL-1β and IL-6 modulate apolipoprotein E gene expression in rat hepatocyte primary culture

Incubation of rat hepatocytes in primary culture with IL-1β at a concentration of 2.5 units/ml resulted in an increase (+80%) in the amount of apoE mRNA without any effect upon apoE synthesis. IL-6 at a low concentration (10 units/ml) induced a decrease (−35%) in the amount of apoE mRNA, but increased apoE synthesis (+28%). No effect was observed with higher concentrations of IL-1β (10 units/ml) or IL-6 (100 units/ml). These results suggest that inflammatory cytokines IL-1β and IL-6 modulate the expression of apoE gene in cultured rat hepatocytes, at a concentration that does not induce the acute phase response

Targeted Learning of The Probability of Success of An In Vitro Fertilization Program Controlling for Time-dependent Confounders

Infertility is a global public health issue and various treatments are available. In vitro fertilization (IVF) is an increasingly common treatment method, but accurately assessing the success of IVF programs has proven challenging since they consist of multiple cycles. We present a double robust semiparametric method that incorporates machine learning to estimate the probability of success (i.e., delivery resulting from embryo transfer) of a program of at most four IVF cycles in the French Devenir Apr`es Interruption de la FIV (DAIFI) study and several simulation studies, controlling for time-dependent confounders. We find that the probability of success in the DAIFI study is 50% (95% confidence interval [0.48, 0.53]), therefore approximately half of future participants in a program of at most four IVF cycles can expect a delivery resulting from embryo transfer

Threshold Regression Models Adapted to Case-Control Studies, and the Risk of Lung Cancer Due to Occupational Exposure to Asbestos in France

Asbestos has been known for many years as a powerful carcinogen. Our purpose is quantify the relationship between an occupational exposure to asbestos and an increase of the risk of lung cancer. Furthermore, we wish to tackle the very delicate question of the evaluation, in subjects suffering from a lung cancer, of how much the amount of exposure to asbestos explains the occurrence of the cancer. For this purpose, we rely on a recent French case-control study. We build a large collection of threshold regression models, data-adaptively select a better model in it by multi-fold likelihood-based cross-validation, then fit the resulting better model by maximum likelihood. A necessary preliminary step to eliminate the bias due to the case-control sampling design is made possible because the probability distribution of being a case can be computed beforehand based on an independent study. The implications of the fitted model in terms of a notion of maximum number of years of life guaranteed free of lung cancer are discussed

The Cellular Prion Protein PrPc Is Involved in the Proliferation of Epithelial Cells and in the Distribution of Junction-Associated Proteins

BACKGROUND: The physiological function of the ubiquitous cellular prion protein, PrP(c), is still under debate. It was essentially studied in nervous system, but poorly investigated in epithelial cells. We previously reported that PrP(c) is targeted to cell-cell junctions of polarized epithelial cells, where it interacts with c-Src. METHODOLOGY/FINDINGS: We show here that, in cultured human enterocytes and in intestine in vivo, the mature PrP(c) is differentially targeted either to the nucleus in dividing cells or to cell-cell contacts in polarized/differentiated cells. By proteomic analysis, we demonstrate that the junctional PrP(c) interacts with cytoskeleton-associated proteins, such as gamma- and beta-actin, alpha-spectrin, annexin A2, and with the desmosome-associated proteins desmoglein, plakoglobin and desmoplakin. In addition, co-immunoprecipitation experiments revealed complexes associating PrP(c), desmoglein and c-Src in raft domains. Through siRNA strategy, we show that PrP(c) is necessary to complete the process of epithelial cell proliferation and for the sub-cellular distribution of proteins involved in cell architecture and junctions. Moreover, analysis of the architecture of the intestinal epithelium of PrP(c) knock-out mice revealed a net decrease in the size of desmosomal junctions and, without change in the amount of BrdU incorporation, a shortening of the length of intestinal villi. CONCLUSIONS/SIGNIFICANCE: From these results, PrP(c) could be considered as a new partner involved in the balance between proliferation and polarization/differentiation in epithelial cells

The proteome of cytosolic lipid droplets isolated from differentiated Caco-2/TC7 enterocytes reveals cell-specific characteristics

Background information. Intestinal absorption of alimentary lipids is a complex process ensured by enterocytes and leading to TRL [TAG (triacylglycerol)-rich lipoprotein] assembly and secretion. The accumulation of circulating intestine-derived TRL is associated with atherosclerosis, stressing the importance of the control of postprandial hypertriglyceridaemia. During the postprandial period, TAGs are also transiently stored as CLDs (cytosolic lipid droplets) in enterocytes. As a first step for determining whether CLDs could play a role in the control of enterocyte TRL secretion, we analysed the protein endowment of CLDs isolated by sucrose-gradient centrifugation from differentiated Caco-2/TC7 enterocytes, the only human model able to secrete TRL in culture and to store transiently TAGs as CLDs when supplied with lipids. Cells were analysed after a 24 h incubation with lipid micelles and thus in a state of CLD-associated TAG mobilization

Sensing of Dietary Lipids by Enterocytes: A New Role for SR-BI/CLA-1

BACKGROUND: The intestine is responsible for absorbing dietary lipids and delivering them to the organism as triglyceride-rich lipoproteins (TRL). It is important to determine how this process is regulated in enterocytes, the absorptive cells of the intestine, as prolonged postprandial hypertriglyceridemia is a known risk factor for atherosclerosis. During the postprandial period, dietary lipids, mostly triglycerides (TG) hydrolyzed by pancreatic enzymes, are combined with bile products and reach the apical membrane of enterocytes as postprandial micelles (PPM). Our aim was to determine whether these micelles induce, in enterocytes, specific early cell signaling events that could control the processes leading to TRL secretion. METHODOLOGY/PRINCIPAL FINDINGS: The effects of supplying PPM to the apex of Caco-2/TC7 enterocytes were analyzed. Micelles devoid of TG hydrolysis products, like those present in the intestinal lumen in the interprandial period, were used as controls. The apical delivery of PPM specifically induced a number of cellular events that are not induced by interprandial micelles. These early events included the trafficking of apolipoprotein B, a structural component of TRL, from apical towards secretory domains, and the rapid, dose-dependent activation of ERK and p38MAPK. PPM supply induced the scavenger receptor SR-BI/CLA-1 to cluster at the apical brush border membrane and to move from non-raft to raft domains. Competition, inhibition or knockdown of SR-BI/CLA-1 impaired the PPM-dependent apoB trafficking and ERK activation. CONCLUSIONS/SIGNIFICANCE: These results are the first evidence that enterocytes specifically sense postprandial dietary lipid-containing micelles. SR-BI/CLA-1 is involved in this process and could be a target for further study with a view to modifying intestinal TRL secretion early in the control pathway

Enterocytes et lipides (controle de l'expression de l'apolipoproteine A-IV et inhibition de la secretion des lipoproteines par les polyphenols de pomme)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

La communication intercellulaire via les jonctions de type GAP chez les kératinocytes humains normaux (une nouvelle cible du vieillissement intrinsèque et actinique ?)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Adhésion et apoptose dans les entérocytes (implication de deux protéines des jonctions cellule-cellule, la E-cadhérine et la protéine cellulaire du prion)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF