The Role of Interleukin-1 Receptor-Associated Kinases in Vogt-Koyanagi-Harada Disease

Purpose

To explore whether IRAK1 and IRAK4 are involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease.

Methods

Thirty-nine VKH patients and thirty-two healthy controls were included in this study. The mRNA levels of IRAK1 and IRAK4 from active VKH patients, inactive VKH patients, and normal controls in peripheral blood mononuclear cells (PBMCs) were detected using real-time quantitative PCR. CD4⁺T cells were purified from PBMCs obtained from active VKH patients and normal controls. The effect of IRAK1/4 inhibition on CD4⁺T cell proliferation following stimulation with IL-18 or IL-1β was measured using a modified MTT assay. CD4⁺T cell expression of IFN-γ and IL-17 were detected by flow cytometry (FCM) and enzyme-linked immunosorbent assay (ELISA). The effect of IRAK1/4 inhibition on NF-κB, STAT1, and STAT3 activation was detected by FCM.

Results

The mRNA levels of IRAK1 and IRAK4 were both significantly increased in active VKH patients compared to inactive VKH patients and healthy controls. No difference in the IRAK1 or IRAK4 mRNA level could be detected between inactive patients and healthy controls. After incubation with IRAK1/4 inhibitor, the proliferation of CD4⁺T cells was inhibited both in the active VKH patients and in the healthy controls. IRAK1/4 inhibition was also associated with a decreased expression of IFN-γ and IL-17. Phosphorylation of NF-κB, STAT1, and STAT3 in CD4⁺T from healthy controls was significantly decreased after inhibition of IRAK1/4.

Conclusions

High mRNA levels of IRAK1 and IRAK4 correlated with VKH disease activity. IRAK1 and IRAK4 play a role in the activation and proliferation of CD4⁺T cells and the higher expression observed in VKH may contribute to the pathogenesis of this blinding condition.     

The Role of Lipotoxicity in Smoke Cardiomyopathy

Background/Aims

Experimental and clinical studies have shown the direct toxic effects of cigarette smoke (CS) on the myocardium, independent of vascular effects. However, the underlying mechanisms are not well known.

Methods

Wistar rats were allocated to control (C) and cigarette smoke (CS) groups. CS rats were exposed to cigarette smoke for 2 months.

Results

After that morphometric, functional and biochemical parameters were measured. The echocardiographic study showed enlargement of the left atria, increase in the left ventricular systolic volume and reduced systolic function. Within the cardiac metabolism, exposure to CS decreased beta hydroxy acyl coenzyme A dehydrogenases and citrate synthases and increased lactate dehydrogenases. Peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) were expressed similarly in both groups. CS increased serum lipids and myocardial triacylglycerols (TGs). These data suggest that impairment in fatty acid oxidation and the accumulation of cardiac lipids characterize lipotoxicity. CS group exhibited increased oxidative stress and decreased antioxidant defense. Finally, the myocyte cross-sectional area and active Caspase 3 were increased in the CS group.

Conclusion

The cardiac remodeling that was observed in the CS exposure model may be explained by abnormalities in energy metabolism, including lipotoxicity and oxidative stress.     

丝裂原活化蛋白激酶和磷酸酯酶-1在心肌病和细胞凋亡中的作用

ERK、JNK和p38等丝裂原活化蛋白激酶通过生长因子、激动剂或应激反应等介导生长、分化、凋亡以及细胞间相互作用等多种过程。ERK、JNK和p38是参与心衰病理过程的主要信号元件,MKP-1是丝裂原活化蛋白激酶等的去磷酸化因子,是一种应激蛋白,在应激反应中可以抑制ERK、JNK和p38的活性,并通过凋节ERK、JNK和p38的活性,参与对心衰病理过程的调节。本文以转基因研究结果为主要线索,对丝裂原活化蛋白激酶和磷酸酯酶．1在心衰病理过程中的作用进行了综述。     

Role of Murine Intestinal Interleukin-1 Receptor 1-Expressing Lymphoid Tissue Inducer-Like Cells in Salmonella Infection

Interleukin (IL)-1 signaling plays a critical role in intestinal immunology. Here, we report that the major population of intestinal lamina propria lymphocytes expressing IL-1 receptor 1 (IL-1R1) is the lymphoid tissue inducer (LTi)-like cell, a type of innate lymphoid cell. These cells are significant producers of IL-22, and this IL-22 production depends on IL-1R1 signaling. LTi-like cells are required for defense against Salmonella enterica serovar Typhimurium. Moreover, colonic LTi-like cell numbers depend on the presence of the intestinal microbiota. LTi-like cells require IL-1R1 for production of protective cytokines and confer protection in infectious colitis, and their cell numbers in the colon depend upon having a microbiome.     

Protective Role of Glutathione Synthesis on Radiation-Induced DNA Damage in Rabbit Brain

1. Radiotherapy has attracted increasing interest in recent years. It is known that ionizing radiation induces oxygen radical injury, whereas oxidative stress by the radiation can cause cellular responses to defense cellular injury. In this study, the metabolism of antioxidants in response to ionizing radiation to the brain was studied in the brain using experimental rabbits.2. Ionizing radiation to the hemicerebrum caused an increase in the levels of glutathione (GSH) and the activity of a GSH synthesizing enzyme, -glutamylcysteine synthetase (-GCS), and Cu,Zn-superoxide dismutase (Cu,Zn-SOD). Ionizing radiation also induced DNA-damage estimated by the formation of 8-hydroxydeoxyguanosine. These changes were dependent on the radiation dose.3. Previous intrathecal-administration of buthionine sulfoximine (100 M), a specific inhibitor of -GCS, increased DNA damage by radiation in the radiated hemicerebrum. That of S-methyl GSH, on the other hand, resulted in a significant reduction of DNA damage by radiation.4. These results suggest that synthesis of GSH and Cu,Zn-SOD is responsive to ionizing radiation and this induction of antioxidants may play a role in reducing tissue damage in radiotherapy.     

Interleukin-1

Interleukin-I (IL-1) is the prototypic pro-inflammatory cytokine. There are two forms of IL-1, IL-1 and IL-Iβ and in most studies, their biological activities are indistinguishable. IL-1 affects nearly every cell type, often in concert with another pro-inflammatory cytokine, tumor necrosis factor (TNF). Although IL-1 can upregulate host defenses and function as an immunoadjuvant, IL-1 is a highly inflammatory cytokine. The margin between clinical benefit and unacceptable toxicity in humans is exceedingly narrow. In contrast, agents that reduce the production and/or activity of IL-1 are likely to have an impact on clinical medicine. The synthesis, processing, secretion and activity of IL-1, particularly IL-Iβ, are tightly regulated events. A unique aspect of cytokine biology is the naturally occurring IL-1 receptor antagonist (IL-1Ra). IL-IRa is structurally similar to IL-Iβ but lacking agonist activity is used in clinical trials to reduce disease severity. In addition, regulation of IL-1 activity extends to low numbers of surface receptors, circulating soluble receptors and a cell surface “decoy” receptor to down-regulate responses to IL-Iβ. This review updates the current knowledge on IL-1.     

白细胞介素-6在肝再生中的作用

白细胞介素-6(IL-6)是一种多功能的细胞因子。近年来发现,它是启动肝细胞增殖的早期信号中不可缺少的组成部分,在肝再生中有重要作用。现对IL-6在肝再生中的作用及可能机制进行综述,为肝脏疾病的治疗提供新的思路。     

Protective Role of R-spondin1, an Intestinal Stem Cell Growth Factor,against Radiation-Induced Gastrointestinal Syndrome in Mice

Background

Radiation-induced gastrointestinal syndrome (RIGS) results from a combination of direct cytocidal effects on intestinal crypt and endothelial cells and subsequent loss of the mucosal barrier, resulting in electrolyte imbalance, diarrhea, weight loss, infection and mortality. Because R-spondin1 (Rspo1) acts as a mitogenic factor for intestinal stem cells, we hypothesized that systemic administration of Rspo1 would amplify the intestinal crypt cells and accelerate the regeneration of the irradiated intestine, thereby, ameliorating RIGS.

Methods and Findings

Male C57Bl/6 mice received recombinant adenovirus expressing human R-spondin1 (AdRspo1) or E.coli Lacz (AdLacz), 1–3 days before whole body irradiation (WBI) or abdominal irradiation (AIR). Post-irradiation survival was assessed by Kaplan Meier analysis. RIGS was assessed by histological examination of intestine after hematoxilin and eosin staining, immunohistochemical staining of BrdU incorporation, Lgr5 and β-catenin expression and TUNEL staining. The xylose absorption test (XAT) was performed to evaluate the functional integrity of the intestinal mucosal barrier. In order to examine the effect of R-spondin1 on tumor growth, AdRspo1 and AdLacZ was administered in the animals having palpable tumor and then exposed to AIR. There was a significant increase in survival in AdRspo1 cohorts compared to AdLacZ (p<0.003) controls, following WBI (10.4 Gy). Significant delay in tumor growth was observed after AIR in both cohorts AdRspo1 and AdLacZ but AdRspo1 treated animals showed improved survival compared to AdLacZ. Histological analysis and XAT demonstrated significant structural and functional regeneration of the intestine in irradiated animals following AdRspo1 treatment. Immunohistochemical analysis demonstrated an increase in Lgr5+ve crypt cells and the translocation of β-catenin from the cytosol to nucleus and upregulation of β-catenin target genes in AdRspo1-treated mice, as compared to AdLacz-treated mice.

Conclusion

Rspo1 promoted radioprotection against RIGS and improved survival of mice exposed to WBI. The mechanism was likely related to induction of the Wnt-β-catenin pathway and promotion of intestinal stem cell regeneration. Rspo1 has protective effect only on normal intestinal tissue but not in tumors after AIR and thereby may increase the therapeutic ratio of chemoradiation therapy in patients undergoing abdominal irradiation for GI malignancies.     

Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

We have reported previously that ocular infection of different strains of mice with recombinant herpes simplex virus 1 (HSV-1) constitutively expressing interleukin-2 (IL-2) provokes central nervous system (CNS) demyelination and optic neuropathy, as determined by changes in visual evoked cortical potentials and pathological changes in the optic nerve and CNS, whereas recombinant viruses expressing IL-4, gamma interferon, IL-12p35, IL-12p40, or IL-12p70 do not induce this neuropathy. The goal of this study was to dissect the mechanism underlying the interplay between the immune system (elevation of IL-2) and an environmental factor (infection with HSV-1) that elicits this pathology. Similar results were obtained upon delivery of IL-2 into the mouse brain using osmotic minipumps or injection of mice with recombinant IL-2 protein, IL-2 DNA, or IL-2 synthetic peptides prior to infection with wild-type (wt) HSV-1 strains McKrae and KOS. The critical role of IL-2 is further supported by our data, indicating that a single mutation at position T27A in IL-2 completely blocks the HSV-1-induced pathology. This study shows a novel model of autoimmunity in which viral infection and enhanced IL-2 cause CNS demyelination.     

白细胞介素-6在酒精性肝病中的作用

酒精性肝病(alcoholic liver disease,ALD)是由于长期过量饮酒导致肝的内部组织发生炎症损伤的慢性肝病.乙醇及其衍生物在代谢过程中直接或间接诱导引起的肝炎症反应可能是ALD发病的重要机制.然而,该过程内在的细胞分子机制尚不明确.最新研究发现,白细胞介素-6(interleukin-6,IL-6)对...     

Role of Interleukin-12 in Primary Influenza Virus Infection

The effect of endogenous interleukin-12 (IL-12) on the influenza virus immune response in BALB/c mice was evaluated. Following primary influenza virus infection, IL-12 mRNA and protein are detected in the lung, with live virus being required for cytokine induction. Endogenous IL-12 contributes to early NK cell-dependent gamma interferon (IFN-γ) production (days 3 and 5) but not late T-cell-dependent IFN-γ secretion (day 7). IL-12 contributes to the inhibition of early virus replication but is not required for virus clearance. IL-12 also modestly contributes to the activation of cytotoxic T lymphocytes. Thus, in this model of experimental influenza virus infection, endogenous IL-12 contributes primarily to the early development and activation of the innate immune response.     

Interleukin-10 Mediated Autoregulation of Murine B-1 B-Cells and Its Role in Borrelia hermsii Infection

B cells are typically characterized as positive regulators of the immune response, primarily by producing antibodies. However, recent studies indicate that various subsets of B cells can perform regulatory functions mainly through IL-10 secretion. Here we discovered that peritoneal B-1 (B-1P) cells produce high levels of IL-10 upon stimulation with several Toll-like receptor (TLR) ligands. High levels of IL-10 suppressed B-1P cell proliferation and differentiation response to all TLR ligands studied in an autocrine manner in vitro and in vivo. IL-10 that accumulated in cultures inhibited B-1P cells at second and subsequent cell divisions mainly at the G1/S interphase. IL-10 inhibits TLR induced B-1P cell activation by blocking the classical NF-κB pathway. Co-stimulation with CD40 or BAFF abrogated the IL-10 inhibitory effect on B-1P cells during TLR stimulation. Finally, B-1P cells adoptively transferred from the peritoneal cavity of IL-10^−/− mice showed better clearance of Borrelia hermsii than wild-type B-1P cells. This study described a novel autoregulatory property of B-1P cells mediated by B-1P cell derived IL-10, which may affect the function of B-1P cells in infection and autoimmunity.     

Suppression of Radiation-Induced Salivary Gland Dysfunction by IGF-1

Background

Radiation is a primary or secondary therapeutic modality for treatment of head and neck cancer. A common side effect of irradiation to the neck and neck region is xerostomia caused by salivary gland dysfunction. Approximately 40,000 new cases of xerostomia result from radiation treatment in the United States each year. The ensuing salivary gland hypofunction results in significant morbidity and diminishes the effectiveness of anti-cancer therapies as well as the quality of life for these patients. Previous studies in a rat model have shown no correlation between induction of apoptosis in the salivary gland and either the immediate or chronic decrease in salivary function following γ-radiation treatment.

Methodology/Principal Finding

A significant level of apoptosis can be detected in the salivary glands of FVB mice following γ-radiation treatment of the head and neck and this apoptosis is suppressed in transgenic mice expressing an activated mutant of Akt (myr-Akt1). Importantly, this suppression of apoptosis in myr-Akt1 mice preserves salivary function, as measured by saliva output, three and thirty days after γ-radiation treatment. In order to translate these studies into a preclinal model we found that intravenous injection of IGF1 stimulated activation of endogenous Akt in the salivary glands in vivo. A single injection of IGF1 prior to exposure to γ-radiation diminishes salivary acinar cell apoptosis and completely preserves salivary gland function three and thirty days following irradiation.

Conclusions/Significance

These studies suggest that apoptosis of salivary acinar cells underlies salivary gland hypofunction occurring secondary to radiation of the head and neck region. Targeted delivery of IGF1 to the salivary gland of patients receiving head and neck irradiation may be useful in reducing or eliminating xerostomia and restoring quality of life to these patients.     

Interleukin-1 and osteoarthritis

Il-1, a multifunctional monokine, can stimulate both synoviocytes and articular chondrocytes to release neutral proteases and prostaglandin E2. It is also capable of promoting bone resorption. Therefore, this molecule (or family of molecules) is likely to play an important role in the mechanism of articular cartilage destruction that occurs in degenerative arthropathies. The synovial tissue itself can produce Il-1 (Catabolin) in some conditions, such as a slight traumatism, so that the presence of local inflammation is not necessary for "Il-1-cartilage" interaction to occur. Fundamental macromolecules of cartilage (collagens, proteoglycans) exert a stimulatory effect on Il-1 production, either as such or in the form of immune complexes. Some activated complement fractions (C3a and C5a) may also be actively involved. Studies on the mechanisms which regulate Il-1 synthesis and release, as well as investigations on the response of target cells to Il-1, are presently fascinating goals that could lead to new strategies in therapeutic research.     

A Role for Interleukin-1 Alpha in the 1,25 Dihydroxyvitamin D3 Response in Mammary Epithelial Cells

Breast cancer is the most common non-cutaneous malignancy in American women, and better preventative strategies are needed. Epidemiological and laboratory studies point to vitamin D₃ as a promising chemopreventative agent for breast cancer. Vitamin D₃ metabolites induce anti-proliferative effects in breast cancer cells in vitro and in vivo, but few studies have investigated their effects in normal mammary epithelial cells. We hypothesized that 1,25(OH)₂D₃, the metabolically active form of vitamin D₃, is growth suppressive in normal mouse mammary epithelial cells. In addition, we have previously established a role for the cytokine interleukin-1 alpha (IL1α) in the anti-proliferative effects of 1,25(OH)₂D₃ in normal prostate cells, and so we hypothesized that IL1α is involved in the 1,25(OH)₂D₃ response in mammary cells. Evaluation of cell viability, clonogenicity, senescence, and induction of cell cycle regulators p21 and p27 supported an anti-proliferative role for 1,25(OH)₂D₃ in mammary epithelial cells. Furthermore, 1,25(OH)₂D₃ increased the intracellular expression of IL1α, which was necessary for the anti-proliferative effects of 1,25(OH)₂D₃ in mammary cells. Together, these findings support the chemopreventative potential of vitamin D₃ in the mammary gland and present a role for IL1α in regulation of mammary cell proliferation by 1,25(OH)₂D₃.     

白细胞介素-1家族与哺乳动物生殖

白细胞介素－1家族在哺乳动物生殖过程中起重要作用。它们调节卵巢和睾丸的生理功能,着床前胚胎和子宫相互作用,胚胎着床能力,同时参与蜕膜化,分娩等多个生殖环节。     

Protection Against Adriamycin-Induced Cardiomyopathy by Carnosine in Rats: Role of Endogenous Antioxidants

The aim of this study was to investigate the effects of carnosine, a biological antioxidant, on the acute cardiac damage induced by a single dose of adriamycin in rats. The experimental design consisted of four groups: Control (saline, i.p.); carnosine (CAR; 10 mg/kg/day, i.p.); adriamycin (ADR; 16 mg/kg on the 14th day, i.p.); carnosine with adriamycin. Carnosine was given 2 weeks before and following adriamycin treatment. Blood samples were collected for analysis of plasma creatine kinase (CK) and plasma antioxidant enzymes, glutathione peroxidase (GSH-Px), Cu, Zn-superoxide dismutase (SOD), and catalase (CAT). The rats were then sacrificed, and the hearts were autopsied for hemodynamic study, ECG, and histopathological examination. Results showed that adriamycin produced evident cardiac damage revealed by hemodynamic change, histological alterations, decreased plasma antioxidant enzymes activities, and increased lipid peroxidation to the control value. Carnosine treatment led to significant attenuation of adriamycin-induced cardiomyopathy revealed by normalization of the LVDP, ST interval, CK, SOD, GSH-Px, CAT, and lipid peroxidation. An increase in oxidative stress and inactivation of SOD, GSH-Px, CAT by a single dose of adriamycin were prevented when carnosine was given 2 weeks before and on the same day adriamycin treatment was administered.