Colon cancer cells produce immunoregulatory glucocorticoids

Glucocorticoids (GC) have important anti-inflammatory and pro-apoptotic activities. Initially thought to be exclusively produced by the adrenal glands, there is now increasing evidence for extra-adrenal sources of GCs. We have previously shown that the intestinal epithelium produces immunoregulatory GCs and that intestinal steroidogenesis is regulated by the nuclear receptor liver receptor homolog-1 (LRH-1). As LRH-1 has been implicated in the development of colon cancer, we here investigated whether LRH-1 regulates GC synthesis in colorectal tumors and whether tumor-produced GCs suppress T-cell activation. Colorectal cancer cell lines and primary tumors were found to express steroidogenic enzymes and regulatory factors required for the de novo synthesis of cortisol. Both cell lines and primary tumors constitutively produced readily detectable levels of cortisol, as measured by radioimmunoassay, thin-layer chromatography and bioassay. Whereas overexpression of LRH-1 significantly increased the expression of steroidogenic enzymes and the synthesis of cortisol, downregulation or inhibition of LRH-1 effectively suppressed these processes, indicating an important role of LRH-1 in colorectal tumor GC synthesis. An immunoregulatory role of tumor-derived GCs could be further confirmed by demonstrating a suppression of T-cell activation. This study describes for the first time cortisol synthesis in a non-endocrine tumor in humans, and suggests that the synthesis of bioactive GCs in colon cancer cells may account as a novel mechanism of tumor immune escape.

Glucocorticoids protect renal mesangial cells from apoptosis by increasing cellular sphingosine-1-phosphate

Neutral ceramidase (NCDase) and sphingosine kinases (SphKs) are key enzymes regulating cellular sphingosine-1-phosphate (S1P) levels. In this study we found that stress factor-induced apoptosis of rat renal mesangial cells was significantly reduced by dexamethasone treatment. Concomitantly, dexamethasone increased cellular S1P levels, suggesting an activation of sphingolipid-metabolizing enzymes. The cell-protective effect of glucocorticoids was reversed by a SphK inhibitor, was completely absent in SphK1-deficient cells, and was associated with upregulated mRNA and protein expression of NCDase and SphK1. Additionally, in vivo experiments in mice showed that dexamethasone also upregulated SphK1 mRNA and activity, and NCDase protein expression in the kidney. Fragments (2285, 1724, and 1126 bp) of the rat NCDase promoter linked to a luciferase reporter were transfected into rat kidney fibroblasts and mesangial cells. There was enhanced NCDase promoter activity upon glucocorticoids treatment that was abolished by the glucocorticoid receptor antagonist RU-486. Single and double mutations of the two putative glucocorticoid response element sites within the promoter reduced the dexamethasone effect, suggesting that both glucocorticoid response elements are functionally active and required for induction. Our study shows that glucocorticoids exert a protective effect on stress-induced mesangial cell apoptosis in vitro and in vivo by upregulating NCDase and SphK1 expression and activity, resulting in enhanced levels of the protective lipid second messenger S1P.

Pulse pressure variation and volume responsiveness during acutely increased pulmonary artery pressure: an experimental study

We found that pulse pressure variation (PPV) did not predict volume responsiveness in patients with increased pulmonary artery pressure. This study tests the hypothesis that PPV does not predict fluid responsiveness during an endotoxin-induced acute increase in pulmonary artery pressure and right ventricular loading.

The Importance of Glucocorticoids in AlcoholDependence and Neurotoxicity

http://onlinelibrary.wiley.com/doi/10.1111/j.1530-0277.2010.01298.x/abstract

The inotropic peptide ?ARKct improves ?AR responsiveness in normal and failing cardiomyocytes through G(??)-mediated L-type calcium current disinhibition

The G(βγ)-sequestering peptide β-adrenergic receptor kinase (βARK)ct derived from the G-protein-coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP signaling has been proposed as the underlying mechanism for increased β-adrenergic receptor (βAR) responsiveness. However, molecular targets mediating improved cardiac contractile performance by βARKct and its impact on G(βγ)-mediated signaling have yet to be fully elucidated.

Adrenal insufficiency after glucocorticoid withdrawal in children with rheumatic diseases

?Glucocorticoids (GCs) are often used for the treatment of rheumatic disorders. However, doses are prescribed, which may suppress the hypothalamic-pituitary-adrenal (HPA) axis. After GC withdrawal, recovery of the HPA axis may be delayed putting the patient at risk for adrenal insufficiency. We assessed adrenal function and factors influencing adrenal responsiveness after termination of GC therapy in paediatric patients with rheumatic diseases.

Biological determinants of responsiveness to growth hormone: pharmacogenomics and personalized medicine

It is becoming most clear that many genes are involved in controlling the regulation of growth. Ultimately however, at the level of growth hormone (GH), the relevant question may be not whether a patient is GH-deficient, but whether he is GH-responsive. As these disturbances can be divided into two gross categories, namely alterations causing subnormal GH secretion and/or those presenting with subnormal GH sensitivity/responsiveness, the main aim of this review is to focus on genes involved in growth regulation leading to short stature caused by an alteration of GH insensitivity/GH responsiveness; in other words, clinical circumstances where individually adapted GH replacement therapy may help to increase height velocity and eventually final height.

Unmyelinated afferents in human skin and their responsiveness to low temperature

In humans, there are different types of cutaneous cold-sensitive afferents responsible for cold sensation and cold pain. Innocuous cold is primarily mediated by a population of slow A delta afferents, based on psychophysical and neurophysiological studies. Noxious cold (usually below 15 degrees C) is mediated, at least in part, by polymodal nociceptors. There is also a population of unmyelinated afferents responsive to innocuous low temperature, some of which also respond to heat, whose sensory function has not been completely defined. A paradoxical hot/burning evoked by cooling is unmasked by A-fibre block, and similar sensations are evoked by applying simultaneous cool and warm stimuli to adjacent skin areas. These unmyelinated fibres activated by innocuous cooling (and heating) may contribute to this hot/burning sensation, along with other thermoregulatory functions.

Colon cancer cells produce immunoregulatory glucocorticoids

Expression or release of immunosuppressive molecules may protect tumor cells from the recognition and destruction by the immune system. New findings indicate that colorectal tumors produce immunoregulatory glucocorticoids and thereby suppress immune cell activation. The nuclear receptor LRH-1 plays a critical role in the regulation of colorectal tumor proliferation and glucocorticoid synthesis.

Rotator cuff muscles lose responsiveness to anabolic steroids after tendon tear and musculotendinous retraction: an experimental study in sheep

Long-standing rotator cuff tendon tearing is associated with retraction, loss of work capacity, irreversible fatty infiltration, and atrophy of the rotator cuff muscles. Although continuous musculotendinous relengthening can experimentally restore muscular architecture, restoration of atrophy and fatty infiltration is hitherto impossible.

Validity and responsiveness of the Core Outcome Measures Index (COMI) for the neck

Patient-orientated outcome questionnaires are essential to evaluate treatment success. To compare different treatments, hospitals, and surgeons, standardised questionnaires are required. The present study examined the validity and responsiveness of the Core Outcome Measurement Index for neck pain (COMI-neck), a short, multidimensional outcome instrument.