Fcγ Receptor Signaling in Phagocytes

Fcgamma receptors are among the best-studied phagocytic receptors. The key features of Fcgamma receptor-mediated phagocytosis include phagocytic cup formation by extensive actin cytoskeletal rearrangements, particle engulfment, and the release of proinflammatory mediators such as cytokines and reactive oxygen species. These events are elegantly regulated by the simultaneous engagement of activating and inhibitory Fcgamma receptors and by intracellular signaling molecules. Extensive studies in the past several years have defined the molecular mechanisms of the phagocytic process. The purpose of this review is to revisit some of the well-established signaling pathways as well as to summarize the new findings in this field.     

Role of β-Adrenergic Receptor Subtypes in Lipolysis

In vitro lipolysis stimulated by low (-)-isopre-naline concentrations (30 nM) in epididymal white adipo-cytes from Sprague-Dawley rats was inhibited at least 60–80% by the specific ₁-antagonists LK 204-545 and CGP 20712A (1 M), suggesting that at these low (10 nM) concentrations of (-)-isoprenaline lipolysis was primarily (80%) but not solely mediated via ₁-adrenergic receptors. Low concentrations (100 nM) of (-)-noradrenaline and formoterol also confirmed a role for ₁-adrenergic receptors in mediating lipolysis at low concentrations of these agonists. At higher agonist concentrations, ₃-adrenergic receptors were fully activated and were the dominant -adrenergic receptor subtype mediating the maximum lipolytic response, and the maximum response was not affected by the ₁-antagonists, demonstrating that the ₃-receptor is capable of inducing maximum lipolysis on its own. Studies of lipolysis induced by the relatively ₂-selective agonist formoterol in the presence of ₁-blockade (1 M CGP 20712A) demonstrated the inability of the ₂-selective antagonist ICI 118-551 to inhibit the residual lipolysis at concentrations of ICI 118-551 1 M. Higher concentrations of ICI 118-551 inhibited the residual formoterol-induced lipolysis competetively, but with low affinity (500-fold lower than its ₂-adrenergic receptor pA ₂, 7.80 ± 0.21), suggesting that formoterol was not acting via ₂-adrenergic receptors. These data are consistent with ₁-adrenergic receptors playing an important role in lipolysis at physiological but not pharmacological concentrations of catecholamines and that ₂-adrenergic receptors play no obvious direct role in mediating -adrenergic receptor agonist-induced lipolysis in vitro. Finally, racemic-SR 59230A, unlike the pure (S, S)-isomer (a ₃-selective antagonist), was found to be a non-selective antagonist at the three -adrenergic receptor subtypes, showing that the other enantiomers have different selectivity.     

Peroxisome Proliferator-Activated Receptor γ and Retinoic Acid Receptor Synergistically Up-Regulate the Tumor Suppressor PTEN in Human Promyeloid Leukemia Cells

Peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoic acid receptors (RARs) have been a focus in chemotherapy for human cancers. The tumor suppressor PTEN plays a pivotal role in the growth of human cancer cells. We investigated whether costimulation of PPARgamma and RAR could synergistically up-regulate PTEN in human leukemia cells and consequently potentiate the inhibition of growth and cell cycle progression of these cells. We found that overexpression of PTEN with the adenoviral vector Ad/PTEN caused growth arrest at the G1 phase of the cell cycle of HL-60 cells. HL-60 cells treated with either a PPARgamma ligand (ciglitazone) or a RAR ligand (all-trans retinoic acid [ATRA]) up-regulated PTEN in HL-60 cells. The 2 compounds in combination showed synergistic effects on PTEN expression at the protein and messenger RNA levels. Moreover, the combination of ciglitazone and ATRA synergistically reduced cell growth rates and cell cycle arrest at the G1 phase. Our results suggest that, PPARgamma and RAR play an important role in controlling the growth of leukemia cells via the up-regulation of PTEN.     

Renin and Prorenin Receptor in Hypertension: What’s New?

The (pro)renin receptor, PRR, was initially characterized as a component of the renin-angiotensin system (RAS). PRR-bound renin and prorenin display increased enzymatic activity, and binding activates intracellular signaling, upregulating the expression of profibrotic proteins. As a consequence, most studies set out to demonstrate a role of PRR in hypertension, cardiovascular and renal diseases, and organ damage, and to identify PRR as a therapeutic target to optimize RAS blockade. The results of animal studies were disappointing and did not convincingly establish PRR as major player in hypertension or in organ damage, although human studies suggested a link between a polymorphism in the PRR gene and blood pressure. New data now suggest that PRR is functionally linked to the vacuolar proton-ATPase and, quite unexpectedly, that PRR is necessary to Wnt signaling pathways that are essential (independently of renin) for adult and embryonic stem cell biology, embryonic development, and diseases including cancer, thereby opening new perspectives on the pathophysiological roles of PRR.     

Interleukin-10 and Interleukin-10–Receptor Defects in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by abdominal pain, bloody diarrhoea, and malabsorption leading to weight loss. It is considered the result of inadequate control of an excessive reaction of the immune system to the resident flora of the gut. Like other primary immunodeficiencies, IL-10 and IL-10 receptor (IL10R) deficiency present with IBD and demonstrate the sensitivity of the intestine to any changes of the immune system. Both IL-10 and IL10R deficiency cause severe early-onset enterocolitis and can be successfully treated by hematopoietic stem cell transplantation (HSCT).     

CB1 – Cannabinoid Receptor Antagonist Effects on Cortisol in Cannabis-Dependent Men

Background: The endocannabinoid system modulates the hypothalamic–pituitary–adrenal (HPA) axis, but the effect of cannabinoid type 1 (CB1) receptor antagonism following chronic CB1 receptor stimulation in humans is unknown. Objectives: To evaluate effects of the CB1 receptor antagonist rimonabant on the HPA axis in cannabis-dependent individuals. Methods: Fourteen daily cannabis smokers received increasingly frequent 20 mg oral Δ9-tetrahydrocannabinol (THC) doses (60–120 mg/day) over 8 days to standardize cannabis tolerance. Concurrent with the last THC dose, double-blind placebo or rimonabant (20 or 40 mg) was administered. Cannabinoid, rimonabant, and cortisol plasma concentrations were measured 1.5 hours prior to rimonabant administration and 2.0, 5.5, and 12.5 hours post-dose. Results: Ten participants completed before premature study termination due to rimonabant’s withdrawal from development. Five participants received 20 mg, three received 40 mg, and two placebo. There was a significant positive association between rimonabant concentration and change in cortisol concentration from baseline (r = .53, p < .01). There also was a borderline significant association between rimonabant dose and cortisol concentrations when the dose-by-time interaction was included. Four of eight participants receiving rimonabant (none of two receiving placebo) had greater cortisol concentrations 2 hours after dosing (at 11:30) than at 08:00, while normal diurnal variation should have peak concentrations at 08:00. Conclusion: Rimonabant 20 or 40 mg did not significantly increase plasma cortisol concentrations, consistent with an absence of antagonist-elicited cannabis withdrawal. Scientific Significance: Rimonabant doses >40 mg might elicit cortisol changes, confirming a role for CB1 receptors in modulating the HPA axis in humans.     

γ-Aminobutyric Acid B Receptor Improves Carbon Tetrachloride-Induced Liver Fibrosis in Rats

Background

It was well known that angiotension II can inhibit hepatic stellate cell activation. The GABA_B receptor was upregulated when the hepatic stellate cell line was stimulated by angiotension II in our previous study. But the role of the GABA_B receptor in liver fibrosis has never been reported.

Aim

In the present study, we investigated the effects of this receptor on carbon tetrachloride-induced liver fibrosis in rats.

Methods

The rats were divided into four groups including GABA_B receptor agonist, antangonist, model and control group. α-smooth muscle actin (α-SMA) and GABA_B receptor expression levels were detected by immunohistochemistry and real-time polymerase chain reaction. Liver function tests were performed once blood samples was taken; Western blot analysis was used to detect protein expression level of α-SMA and TGF-β1.

Results

We found baclofen ameliorated the CCl₄-induced rats’s liver fibrosis. The highest liver enzymes and α-SMA protein levels were found in the CGP35348 group.

Conclusion

The GABA_B receptor may have a protective role in the liver.     

Therapeutic Value of Estrogen Receptor α in Hepatocellular Carcinoma Based on Molecular Mechanisms

The incidence of hepatocellular carcinoma (HCC) is signifi-cantly lower in women than men, implying that estrogen receptors (ERs) may play an important role in ...     

Toll-like Receptor 2 (TLR) −196 to 174del Polymorphism in Gastro-duodenal Diseases in Japanese Population

Toll-like receptors (TLRs) play important roles in the signaling of many pathogen-related molecules and endogenous proteins associated with immune activation. −196 to −174del polymorphism affects the TLR2 gene and alters its promoter activity. We investigated the influence of TLR2 −196 to −174del polymorphism on the risk of gastro-duodenal diseases, on the severity of Helicobacter pylori-induced gastritis in a Japanesepopulation. The study was performed on 309 patients with abdominal discomfort and 146 healthy controls. −196 to −174del polymorphism of TLR2 was investigated by allele-specific polymerase chain reaction method in all of the subjects. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system in H. pylori-positive subjects (n = 156). Patients with abdominal discomfort was consisted of 80 gastric ulcers (25.9%), 38 duodenal ulcers (12.3%), five gastric + duodenal ulcers (1.6%), 105 patients with gastritis (34.0%) and 81 normal healthy stomachs (26.2%). We did not find any association between TLR2 polymorphism and risk of gastric ulcer, duodenal ulcer, gastric and duodenal ulcer and gastritis compared to healthy controls. However, the TLR2−196 to −174ins allele was associated with severity of intestinal metaplasia in more than 60 years of ages (P = 0.02). The same allele also increased the risks of developing more severe gastric mucosal atrophy and intestinal metaplasia in female subjects (P < 0.05, P = 0.07 respectively). No association was observed between TLR2 polymorphism and severity of neutrophil and mononuclear cell infiltration. Our data suggest that the TLR2−196 to −174ins allele was associated with more severe intestinal metaplasia in patients older than was correlated with severity of gastric mucosal atrophy and intestinal metaplasia in female subjects.     

Natural Interferon α Treatment and Interferon α Receptor 2 Levels in Acute Hepatitis C

Efficacy of interferon (IFN) therapy during the acute phase of hepatitis C infection is promising, although the optimal regimen has yet to be determined. It is not known whether the known prognostic factors for chronic hepatitis C (CHC) influence the effect of IFN in acute hepatitis C (AHC). Seventeen patients with AHC were analyzed for hepatic IFN alpha receptor 2 (IFNAR2) prior to IFN treatment. All patients were subsequently treated with either 168 million units (MU) or 336 MU of natural IFN alpha. Seventeen age-matched samples of CHC were provided as controls. The overall sustained response rate was 64.7% (11/17). In patients who received a total dose of 168 MU IFN, the sustained response rate was 28.6% (2/7), and in those who received 336 MU of IFN, the sustained response rate was 90.0% (9/10). The peaks of ALT and HCV-RNA quantity were not associated with the response to IFN. The hepatic IFNAR2 levels were 1.52 +/- 0.34 densitometry units and 0.92 +/- 0.16 in AHC and CHC, respectively (P = 0.042). There was no difference in hepatic IFNAR2 levels between sustained virological responders (SVR) and nonsustained virological responders (NR). The hepatic receptor levels were higher in AHC than in CHC patients. The levels of hepatic IFNAR2 did not differ in SVR and NR, indicating that high-dose natural IFN alpha treatment is effective for AHC, irrespective of the levels of hepatic IFNAR2.     

Association of β2-Adrenergic Receptor Polymorphisms with Asthma in a North Indian Population

Background

β₂-Adrenergic receptor (β₂AR), a G-protein coupled receptor, is present on the bronchial smooth muscle cells and results in bronchodilation upon activation. The genetic factors determining β₂AR expression and function may not only alter the response of an individual to the therapy but also may serve as predictive markers for response to the agonists used in the therapy. The present study aimed at evaluating the role of β₂AR-16 and β₂AR-27 gene polymorphisms in asthma.

Methods

A case–control study was performed with a total of 824 adult subjects, including 410 asthmatics and 414 healthy controls from regions of North India. The β₂AR-16 and β₂AR-27 polymorphisms were genotyped by PCR–RFLP.

Results

Statistical analysis for the β₂AR-16 polymorphism revealed that the mutant Gly16 allele was significantly associated with asthma, with OR?=?0.80, 95?% CI?=?0.65–0.99, and P?=?0.032. The Gly16/Gly16 mutant genotype also confers decreased risk toward asthma, with OR?=?0.65, 95?% CI?=?0.41–1.02, and P?=?0.049. However, the β₂AR-27 polymorphism was not associated with asthma as it did not reach statistical significance, with OR?=?0.86, 95?% CI?=?0.69–1.07, and P?=?0.163.

Conclusion

The β₂AR-16 polymorphism confers a decreased risk toward asthma while the β₂AR-27 polymorphism is not associated with asthma in the studied North Indian population.     

Collagen Type Iα1 and Vitamin D Receptor Polymorphisms in Diffuse IdiopathicSkeletal Hyperostosis

Clinical Rheumatology -     

Up and Down Expression of Androgen Receptor, Estrogen Receptor beta and Platelet Derived Growth Factor beta by Testosterone in Aortic Vascular Smooth Muscle Tissues

INTRODUCTIONCoronary heart disease (CHD) is the primary cause of death and disability. Numerous clinical and epidemiological reports demonstrate that men are gener- ally more susceptible to CHD than their female counter- parts. Increasing evidence accumulates that estrogen and perhaps progesterone have a favorable effect on fe- male cardiovascular risk and atherogenic processes. 1 - 4 Much less work, however , has addressed the possi- ble effects of androgens on atherogenesis , 5 and th…     

The Thromboxane Receptor Antagonist S18886 influence the stability of atherosclerosis in ApoE Null Mice

Objectives To investigate whether thromboxane receptor antagonist S18886 inhibits infiltrating macrophages to vessel wall and influence the morphology of atherosclerotic plaque;The effective of S18886 compared to clopidegrol on the development of atherosclerosis, accumulation of lipidfilled macropha-ges in apoE null mice. Methods All mice were done cuffed common carotid artery and fed a Western-type atherogenic diet for 6 weeks from the day of surgery, at same time the therapy group mice were garaged S18886 5mg/Kg/day and clopidegrol respectively, the same volume water were garaged as the placebo group. Results profound inhibition of lesion area growth after cuff of the right common carotid artery in mice with 5mg/kg of S18886, markdely reduce intima to media ratio and intima to total wall area compare with clopidegrol or blank group; Macrophage infiltration into sites of arterial plaque was also markedly attenuated by ICAM-1 deficiency in the S18886 group, whereas inside the arterial wall plaque of placebo apoE null mice α-smooth muscle actin markedly attenuated. Treatment with 25mg/kg/day clopidegrol reduced the level of ICAM-1 staining, both S18886 and clopidegrol didn‘t influence the α-smooth muscle actin inside plaque. Conclusions It was considered that the novel anti-thrombotic drug significant reduce macrophage infiltration in the sites of arterial plaque by ICAM-1 deficiency, S18886 not only reduce the size, but also stabilized the plaque.