IRE1β Inhibits Chylomicron Production by Selectively Degrading MTP mRNA

SummaryMicrosomal triglyceride transfer protein (MTP) is needed to assemble chylomicrons in the endoplasmic reticulum (ER) of enterocytes. We explored the role of an ER stress protein, inositol-requiring enzyme 1β (IRE1β), in regulating this process. High-cholesterol and high-fat diets decreased intestinal IRE1β mRNA in wild-type mice. Ire1b−/− mice fed high-cholesterol and high-fat diets developed more pronounced hyperlipidemia because these mice secreted more chylomicrons and expressed more intestinal MTP, though not hepatic MTP, than wild-type mice did. Chylomicron secretion and MTP expression also were increased in primary enterocytes isolated from cholesterol-fed Ire1b−/− mice. There was no correlation between ER stress and MTP expression. Instead, cell culture studies revealed that IRE1β, but not its ubiquitous homolog IRE1α, decreased MTP mRNA through increased posttranscriptional degradation. Conversely, knockdown of IRE1β enhanced MTP expression. These studies show that IRE1β plays a role in regulating MTP and in chylomicron production

Role of Interleukin 17 in arthritis chronicity through survival of synoviocytes via regulation of synoviolin expression

Background: The use of TNF inhibitors has been a major progress in the treatment of chronic inflammation. However, not all patients respond. In addition, response will be often lost when treatment is stopped. These clinical aspects indicate that other cytokines might be involved and we focus here on the role of IL-17. In addition, the chronic nature of joint inflammation may contribute to reduced response and enhanced chronicity. Therefore we studied the capacity of IL-17 to regulate synoviolin, an E3 ubiquitin ligase implicated in synovial hyperplasia in human rheumatoid arthritis (RA) FLS and in chronic reactivated streptococcal cell wall (SCW)-induced arthritis.<p></p> Methodology/Principal Findings: Chronic reactivated SCW-induced arthritis was examined in IL-17R deficient and wild-type mice. Synoviolin expression was analysed by real-time RT-PCR, Western Blot or immunostaining in RA FLS and tissue, and p53 assessed by Western Blot. Apoptosis was detected by annexin V/propidium iodide staining, SS DNA apoptosis ELISA kit or TUNEL staining and proliferation by PCNA staining. IL-17 receptor A (IL-17RA), IL-17 receptor C (IL-17-RC) or synoviolin inhibition were achieved by small interfering RNA (siRNA) or neutralizing antibodies. IL-17 induced sustained synoviolin expression in RA FLS. Sodium nitroprusside (SNP)-induced RA FLS apoptosis was associated with reduced synoviolin expression and was rescued by IL-17 treatment with a corresponding increase in synoviolin expression. IL-17RC or IL-17RA RNA interference increased SNP-induced apoptosis, and decreased IL-17-induced synoviolin. IL-17 rescued RA FLS from apoptosis induced by synoviolin knockdown. IL-17 and TNF had additive effects on synoviolin expression and protection against apoptosis induced by synoviolin knowndown. In IL-17R deficient mice, a decrease in arthritis severity was characterized by increased synovial apoptosis, reduced proliferation and a marked reduction in synoviolin expression. A distinct absence of synoviolin expressing germinal centres in IL-17R deficient mice contrasted with synoviolin positive B cells and Th17 cells in synovial germinal centre-like structures.<p></p> Conclusion/Significance: IL-17 induction of synoviolin may contribute at least in part to RA chronicity by prolonging the survival of RA FLS and immune cells in germinal centre reactions. These results extend the role of IL-17 to synovial hyperplasia.<p></p&gt

Correlation between SiO v = 3 J = 1 → 0 maser excitation and the light curve of a long-period variable star

In order to understand the excitation mechanisms of silicon monoxide (SiO) masers around long-period variables (LPVs), we have investigated distributions of the SiO v = 2 and v = 3 J = 1 → 0 masers around 12 LPVs by very long baseline interferometry (VLBI) observations with the VLBI Exploration of Radio Astrometry (VERA) and the Nobeyama 45 m telescopes. VLBI fringes of the v = 3 maser emission were detected for five LPVs. The composite maps of the v = 2 and v = 3 masers were made for T Cep, W Hya, WX Psc, and R Leo using the spectral line phase-referencing technique. The v = 2 maser spots were distributed in a ring-like form around the central stars, while it is difficult to recognize any specific morphology in the v = 3 maser distributions due to the small number of v = 3 spots detected. However in T Cep, we find that the distribution of the v = 3 maser spots correlates well with the v = 2 masers within a few milliarcseconds (0.2-0.3 au) in position and 1 km s-1 in line-of-sight velocity at the light curve phase of θ = 0.28 (θ = 0.0 and 1.0 correspond to the visible light maxima). This correlation implies that the mechanism of line-overlapping between the mid-infrared lines of H2O and SiO molecules works in T Cep at θ = 0.28. We discuss the possibility that the line-overlapping may work at the limited duration from the maximum to the minimum of the stellar light curve. © 2018 The Author(s)

Roles of IP3R and RyR Ca2+ Channels in Endoplasmic Reticulum Stress and β-Cell Death

OBJECTIVE—Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of diabetes, but the roles of specific ER Ca2+ release channels in the ER stress–associated apoptosis pathway remain unknown. Here, we examined the effects of stimulating or inhibiting the ER-resident inositol trisphosphate receptors (IP3Rs) and the ryanodine receptors (RyRs) on the induction of β-cell ER stress and apoptosis

JunB Inhibits ER Stress and Apoptosis in Pancreatic Beta Cells

Cytokines contribute to pancreatic β-cell apoptosis in type 1 diabetes (T1D) by modulation of β-cell gene expression networks. The transcription factor Activator Protein-1 (AP-1) is a key regulator of inflammation and apoptosis. We presently evaluated the function of the AP-1 subunit JunB in cytokine-mediated β-cell dysfunction and death. The cytokines IL-1β+IFN-γ induced an early and transitory upregulation of JunB by NF-κB activation. Knockdown of JunB by RNA interference increased cytokine-mediated expression of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum (ER) stress markers, leading to increased apoptosis in an insulin-producing cell line (INS-1E) and in purified rat primary β-cells. JunB knockdown β-cells and junB−/− fibroblasts were also more sensitive to the chemical ER stressor cyclopiazonic acid (CPA). Conversely, adenoviral-mediated overexpression of JunB diminished iNOS and ER markers expression and protected β-cells from cytokine-induced cell death. These findings demonstrate a novel and unexpected role for JunB as a regulator of defense mechanisms against cytokine- and ER stress-mediated apoptosis