Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis

Background

Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma.

Insights into the diagnosis and pathogenesis of the antiphospholipid syndrome

The Antiphospholipid syndrome (APS), formerly known as Anticardiolipin or Hughes syndrome, is a systemic autoimmune disorder characterized by obstetrical complications and thrombotic events affecting almost every organ-system in patients persistently testing positive for antiphospholipid antibodies (aPL). The contribution of the extra-criteria aPL to the pathogenesis of APS have exceeded the expectations of a simple, direct pathologic ‘hit’ leading to thrombogenesis or obstetrical complications, and more pathologic pathways are being linked directly or indirectly to aPL. The value of extra-criteria aPL is on the rise, and these antibodies are nowadays evaluated as markers for risk assessment in the diagnostic approach to APS. A diagnosis of APS should be considered in pediatric patients with suggestive clinical and laboratory picture. Management of APS remains mostly based on anticoagulation, while other drugs are being tested for efficacy and side effects. Low-dose aspirin may have a role in the management of thrombotic and obstetric APS. Due to the high variability in disease severity and complication recurrence outcomes, new tools are being developed and validated to assess the damage index and quality of life of APS patients.     

Meta‐analysis of association between cytokine gene polymorphisms and Behcet's disease risk

The aim of this study was to perform a meta‐analysis of eligible studies to derive precise estimation of the association of interleukin‐1 (IL‐1), IL‐10 and tumor necrosis factor (TNF)‐α polymorphisms with Behcet's disease (BD). Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. A total of 4003 cases and 4748 controls in 19 eligible studies were included in the meta‐analysis. We examined the relationship between seven single nucleotide polymorphisms (SNPs) in the above‐mentioned three cytokine genes and susceptibility to BD. Meta‐analysis indicated the association between the cytokine gene polymorphisms in all study subjects in the allelic model (TNF‐α ‐308A/G: OR = 0.73, 95% CI: 0.61–0.88, P = 0.001; IL‐10 ‐819C/T: OR = 0.72, 95% CI: 0.66–0.78, P < 0.001; IL‐10 ‐592C/A: OR = 0.74, 95% CI: 0.64–0.86, P < 0.001); the dominant model (TNF‐α ‐308A/G: OR = 0.77, 95% CI: 0.64–0.92, P = 0.004; IL‐10 ‐1082G/A: OR = 1.64, 95% CI: 1.10–2.44, P = 0.014); the recessive model (TNF‐α ‐308A/G: OR = 0.27, 95% CI: 0.12–0.65, P = 0.003; IL‐10 ‐819C/T: OR = 0.71, 95% CI: 0.57–0.90, P = 0.004). However, no significant evidence for the associations of IL‐1α ‐889C/T, IL‐1β ‐551C/T, IL‐1β ‐3962C/T polymorphisms with BD susceptibility was detected. The present study might suggest that TNF‐α ‐308A/G, IL‐10 ‐1082G/A, ‐819C/T, ‐592C/A polymorphisms are associated with BD susceptibility.     

Protection against liver injury by PGE1 or anti‐TNF‐α is associated with a reduction of TNF‐R1 expression in hepatocytes

Background: Tumour necrosis factor‐α (TNF‐α) has been shown to exacerbate or protect against liver injury in different experimental models. In a previous study, we observed that enhancement of TNF‐α expression in hepatocytes by prostaglandin E ₁ (PGE ₁ ) pre‐administration induced iNOS expression and cytoprotection against experimental liver injury in rats. Nevertheless, the reduction of TNF‐α bioactivity by anti‐TNF‐α antibodies also reduced liver injury by D‐GalN. The purpose of the present study was to evaluate whether protection by PGE ₁ or anti‐TNF‐α was related to a common effect on the membrane‐bound TNF‐α receptor expression. Methods: Liver injury was induced in male Wistar rats by intraperitoneal injection of D‐galactosamine (D‐GalN) (1?g/kg). PGE ₁ or anti‐TNF‐α was administered at 30 or 60?min before D‐GalN, respectively. Liver injury was evaluated by alanine aminotransferase (ALT) activity in serum and histological examination in liver sections. TNF‐αwas determined by ELISA in serum. The expression of TNF‐α receptor type 1 (TNF‐R1) and TNF‐α receptor type 2 (TNF‐R2) in hepatocytes was assessed by immunohistochemistry and immunoprecipitation?+?Western‐blot analysis. Results: PGE ₁ or anti‐TNF‐α reduced liver injury induced by D‐GalN. Although PGE ₁ enhanced and anti‐TNF‐α reduced TNF‐α concentration in serum, both protective treatments reduced the expression of TNF‐R1 in hepatocytes. TNF‐R2 was not detected in our experimental conditions. Conclusions: Our study showed that reduction of liver injury by PGE ₁ or anti‐TNF‐α antibodies was related to a reduction of TNF‐R1 expression in hepatocytes.     

Effect of interleukin-6 receptor inhibitor,tocilizumab, in preventing joint destruction in patients with rheumatoid arthritis showing inadequate response to TNF inhibitors

Abstract

Objectives. To examine the effectiveness of tocilizumab (TCZ) in preventing joint destruction in patients with inadequate response to tumor necrosis factor inhibitors (TNF-IR) by assessing X-rays.

Methods. RA patients were extracted from the Retrospective actemra investigation for optimal needs of RA patients (REACTION) study. Parameters and components of disease activity were evaluated during anti-TNF treatment and during TCZ treatment. X-ray images of hands and feet at the beginning of this study during anti-TNF treatment (Pre), at the start point of TCZ treatment (Baseline) and after TCZ treatment (Post) were collected for assessing joint destruction.

Results. Forty-five patients from the REACTION study fulfilled the criteria of clinical TNF-IR. During anti-TNF treatment, mean DAS28-ESR rose from 5.35 to 5.87 (mean observation duration, 16 months) but improved significantly to 2.94 (P < 0.0001) at 52 weeks after switching to TCZ. Mean change in van der Heijde-modified Sharp score (TSS) during anti-TNF treatment was 3.17 in this TNF-IR population. After switching to TCZ, mean change in TSS was 1.20 (P < 0.05). Rate of radiographic non-progression improved to 66.7% during TCZ treatment from 40.0% during anti-TNF treatment. The predictive factor for no radiographic progression after switching to TCZ was a HAQ disability index (HAQ-DI) score of ≤ 1.88 at switching to TCZ.

Conclusion. TCZ was a good treatment option for improving signs and symptoms and inhibiting progression of joint damage in patients with clinical and structural TNF-IR.     

Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice

BACKGROUND & AIMS: Interleukin-10 knockout (IL-10(-/-)) mice spontaneously develop colitis characterized by T-helper cell type 1-polarized inflammation. We tested the possible therapeutic activity of the peroxisome proliferator-activated receptor alpha (PPARalpha) ligand fenofibrate, and the PPARdelta ligand GW0742, in IL-10(-/-) mice and investigated the cellular/molecular mechanisms for fenofibrate action. METHODS: The effect of fenofibrate or GW0742 on the progression of colitis in C3H.IL-10(-/-) mice was evaluated. Effects of fenofibrate on cytokine and chemokine gene expression were studied in cultured splenocytes, pathogenic T cells isolated from C3H/HeJBir mice, and HT-29 colorectal cancer cells. RESULTS: Treatment of C3H.IL-10(-/-) mice with fenofibrate delayed the onset of colitis, decreased the colonic histopathology score, and decreased colonic expression of genes encoding the inflammatory cytokines interferon-gamma and interleukin (IL)-17. The target for fenofibrate, PPARalpha, was expressed in lymphocytes, macrophages, and crypt and surface epithelial cells of the colon. The mean number of lymphocytes was decreased by more than 75% in colonic sections of fenofibrate-treated as compared with control IL-10(-/-) mice, and fenofibrate repressed interferon-gamma and IL-17 expression in isolated T cells. Fenofibrate also repressed the expression of the genes encoding 3 chemokines, CXCL10, CCL2, and CCL20, and repressed CXCL10 gene promoter activity in tumor necrosis factor-alpha-treated HT-29 cells. In contrast to the beneficial effect of fenofibrate, the PPARdelta ligand GW0742 accelerated the onset of colitis in IL-10(-/-) mice. CONCLUSIONS: The immunopathology observed in IL-10(-/-) mice resembles that seen in Crohn's disease. The novel therapeutic activity of fenofibrate in this mouse model suggests that it may also have activity in Crohn's disease.     

Intestinal barrier dysfunction and increased COX-2 gene expression in the gut of elderly rats with acute pancreatitis

Background/ObjectivesThe clinical course of acute pancreatitis can vary from mild to severe. In its most severe manifestation, acute pancreatitis is associated with an exacerbated systemic inflammatory response and high mortality rates. The severe form of acute pancreatitis is more frequent in elderly patients than in young patients, but the mechanisms underlying this difference are still under investigation.MethodsRats were divided into two groups as follows: Group 1, young rats; and Group 2, old rats. Acute pancreatitis group was induced by a retrograde injection of a sodium taurocholate solution into the biliopancreatic duct. Using this model of acute pancreatic injury, we designed a study to investigate possible differences in microbial translocation and characteristics of the intestinal barrier between elderly and young rats.ResultsThere was a significantly higher number of bacterial colonies in the pancreas of elderly rats compared with young rats following pancreas injury, which was associated with a more severe local intestinal inflammatory response that included elevated gene expression of COX-2 and a decreased gene expression of tight junction proteins.ConclusionsWe conclude that intestinal damage during acute pancreatitis is exacerbated in elderly rats compared with young rats and that COX-2 inhibition could be a potential therapeutic target to offer tailored treatment for acute pancreatitis in the elderly.     

Modulation of Kupffer cell and peripheral blood monocyte activity by in vivo treatment of rats with all-trans-retinol

Abstract: Previous studies have shown that large doses of vitamin A potentiate chemical-induced liver injury and that the Kupffer cell is directly involved in this potentiation. Therefore, these studies were designed to determine if Kupffer cells isolated from vitamin A treated male Sprague-Dawley rats (75 mg/kg/day for 3–7 days as all- trans-retinol) had altered activity and function. Respiratory activity of Kupffer cells isolated from rats treated with vitamin A for 3 to 7 days markedly increased. Similarly, phagocytic activity was significantly elevated (up to 9-fold) after exposure to vitamin A for 3 to 7 days. Production of reactive oxygen species, measured by luminol-enhanced chemiluminescence of Kupffer cells isolated after 7 days of vitamin A exposure, was significantly higher than that of control cells when stimulated with opsonized zymosan. Also, the release of superoxide anion by individual Kupffer cells isolated from vitamin A treated rats was nearly three times greater than that of control cells. Basal production of tumor necrosis factor-alpha (TNF-α) and prostaglandin E2 (PGE₂) production were significantly elevated in Kupffer cells isolated from rats treated with vitamin A. Lastly, peripheral blood monocytes (PBMC) isolated from rats treated with vitamin A for 7 days had a significantly greater respiratory activity, as well as TNF-α and PGE₂ production, than PBMC isolated from control rats. Our data suggest that large doses of vitamin A enhance both Kupffer cell and PBMC function. Upregulation of the activity by these phagocytic cells may play a role in the vitamin A potentiation of chemical-induced liver injury.