The role of type I interferons and other cytokines in dermatomyositis.
Creator
Arshanapalli Ashish; Shah Mihir; Veerula Vindhya; Somani Ally-Khan
Publisher
Cytokine
Date
2015
2015-06
Description
Much work has been done to unveil the mechanisms behind the pathogenesis of dermatomyositis (DM) - mainly those involving certain pathogenic cytokines, termed "pathokines" as the principal cytokines involved. Recently, it has become clear that a group of cytokines known as type I interferons (IFN-Is) play a significant role in the development of DM. We review the literature published between 1946 and 2014 using an Ovid Medline database search to provide an update on the role of IFN-Is and other cytokines in the pathogenesis of DM. We provide information about the genes and proteins induced by IFN-Is and potential mechanisms by which these downstream products relate to clinical disease activity. We also explore findings of other autoimmune phenomena that may contribute to disease onset and activity including T-helper 17 (Th17) cells and associated interleukins, as well as autoantibodies. Finally, we provide a brief update on current treatment options for DM as well as some new immunomodulatory treatment modalities in development.
Subject
Autoantibodies/immunology; Biological; Cytokines; Dermatomyositis; Dermatomyositis/*immunology/physiopathology/therapy; Humans; Inflammatory myopathy; Interferon Type I/*metabolism; Models; Pathogenesis; Signal Transduction; Type I interferons
Modulation of ten-eleven translocation 1 (TET1), Isocitrate Dehydrogenase (IDH) expression, alpha-Ketoglutarate (alpha-KG), and DNA hydroxymethylation levels by interleukin-1beta in primary human chondrocytes.
Creator
Haseeb Abdul; Makki Mohammad Shahidul; Haqqi Tariq M
Publisher
The Journal of biological chemistry
Date
2014
2014-03
Description
5-Hydroxymethylcytosine (5-hmC) generated by ten-eleven translocation 1-3 (TET1-3) enzymes is an epigenetic mark present in many tissues with different degrees of abundance. IL-1beta and TNF-alpha are the two major cytokines present in arthritic joints that modulate the expression of many genes associated with cartilage degradation in osteoarthritis. In the present study, we investigated the global 5-hmC content, the effects of IL-1beta and TNF-alpha on 5-hmC content, and the expression and activity of TETs and isocitrate dehydrogenases in primary human chondrocytes. The global 5-hmC content was found to be approximately 0.1% of the total genome. There was a significant decrease in the levels of 5-hmC and the TET enzyme activity upon treatment of chondrocytes with IL-1beta alone or in combination with TNF-alpha. We observed a dramatic (10-20-fold) decrease in the levels of TET1 mRNA expression and a small increase (2-3-fold) in TET3 expression in chondrocytes stimulated with IL-1beta and TNF-alpha. IL-1beta and TNF-alpha significantly suppressed the activity and expression of IDHs, which correlated with the reduced alpha-ketoglutarate levels. Whole genome profiling showed an erasure effect of IL-1beta and TNF-alpha, resulting in a significant decrease in hydroxymethylation in a myriad of genes including many genes that are important in chondrocyte physiology. Our data demonstrate that DNA hydroxymethylation is modulated by pro-inflammatory cytokines via suppression of the cytosine hydroxymethylation machinery. These data point to new mechanisms of epigenetic control of gene expression by pro-inflammatory cytokines in human chondrocytes.
Adolescents with urinary stones have elevated urine levels of inflammatory mediators
Creator
Kusumi Kirsten; Ketz John; Saxena Vijay; Spencer John David; Safadi Fayez; Schwaderer Andrew
Publisher
Urolithiasis
Date
2019
2019-04
Description
Urinary stones are increasing in children, primarily during adolescence. Although urinary stones are often viewed in the context of intermittent stone events, increasing evidence indicates that stones are a metabolic process associated with chronic kidney disease and cardiovascular disease. These aforementioned stone-associated conditions may have pediatric origins. To compare urine inflammatory markers in otherwise healthy stone forming children versus matched controls. Urine samples were collected from 12 adolescents with urinary stones along with 15 controls. The levels of 30 urine cytokines were measured using a Mesoscale 30-Plex Human Cytokine panel and normalized to urine creatinine levels. Macrophage inflammatory protein 1β and interleukin 13 levels were significantly elevated in the urine of the stone forming adolescents compared to controls. Interleukin 17A was elevated in the urine of controls. This study indicates that urine levels of cytokines involved in chronic inflammation and fibrosis are elevated in urinary stone formers as early as adolescence. Because stone formers are at risk for chronic kidney disease, macrophage inflammatory protein 1β and interleukin 13 represent investigative targets.
Porterfield V M; Gabella K M; Simmons M A; Johnson J D
Publisher
Brain Behavior and Immunity
Date
2012
2012-11
Description
It has been proposed that increased brain cytokines during repeated stressor exposure can contribute to neuropathological changes that lead to the onset of depression. Previous studies demonstrate that norepinephrine acting via beta-adrenergic receptors (beta-ARs) mediate brain IL-1 production during acute stressor exposure. The aim of the current studies was to examine how the regulation of brain cytokines by adrenergic signaling might change following repeated stressor exposure. Fischer rats were exposed to four days of chronic mild stress and 24 h after the last stressors beta-AR expression, norepinephrine turnover, and beta-AR-mediated induction of brain IL-1 were measured in limbic areas (e.g. hypothalamus, hippocampus, amygdala, and prefrontal cortex) and brainstem. Repeated stressor exposure resulted in decreases in beta-AR expression (B-max) measured by saturation binding curves in many limbic brain areas, while an increase was observed in the brainstem. This coincided with significant increases in norepinephrine turnover in the prefrontal cortex, hypothalamus, and amygdala, a significant increase in norepinephrine turnover was not observed in the hippocampus or brainstem. Stress increased overall IL-1 production in the amygdala (both basal and stimulated). While stress did not affect basal IL-1 levels in any other brain area, central administration of isoproterenol (a beta-AR agonist) augmented IL-1 production in the hypothalamus of stressed animals. These data indicate that repeated stressor exposure results in brain area specific enhancements in beta-AR-mediated IL-1 production and extends current knowledge of stress-induced enhancement of brain cytokine beyond sensitized response to immunological stimuli. (C) 2012 Elsevier Inc. All rights reserved.