Articles That Use the Tag Name:

proinflammatory cytokine

T Cell Chemokine Receptor Patterns as Pathogenic Signatures in Autoimmunity

Abstract: Autoimmune diseases arise from aberrant activation of immune cells directed against endogenous autoantigens expressed throughout the human body. While the initiating triggers remain poorly understood, the self-perpetuating phase of these diseases is directly linked to the ongoing recruitment of inflammatory cells that traffic to the affected anatomical sites. T lymphocytes are prominent drivers of many autoimmune diseases and the targeted trafficking of these cells to infiltrate the affected organs is often a common denominator. The regulation of T cell trafficking involves the coordinated expression of specific patterns of chemokines and the reciprocal expression of cognate chemokine receptors on T cell membranes. Thereby, chemokines direct the specific trafficking of a wide array of responsive activated immune cells. Specific patterns of chemokine receptor expression can correlate with disease activity in an autoimmune disease, confirming the importance of further characterizing the T cells that infiltrate specific sites of autoimmunity. Herein, we will review our current understanding of the roles of chemokines in two common autoimmune diseases: rheumatoid arthritis and multiple sclerosis. We also discuss the implications for chemokine receptor signatures in autoimmune pathogenesis, and how these may provide novel targets for therapeutic intervention. ... Read more

Epigenetics in Atherosclerosis: a Clinical Perspective

Abstract: Significant progress has been made in understanding in the pathogenesis of atherosclerosis. Nevertheless, atherosclerosis remains a great threat to human health worldwide. Epigenetic mechanisms, which involve DNA methylation, histone modification, and microRNA, have significantly enhanced our understanding of the pathological process of atherosclerosis. More importantly, epigenetic processes (in contrast to genetic alterations) are reversible and thus provide a potential therapeutic target in atherosclerosis treatment. Both in vitro and in vivo studies using drugs targeting enzymes involved in epigenetic modifications have shown considerable promise in atherosclerosis treatment. This review aims to present an overview of current epigenetic mechanisms involved in the pathogenesis of atherosclerosis, and discuss points in these processes where therapeutic interventions likely bear fruition. ... Read more

Why Is Coinfection with Influenza Virus and Bacteria So Difficult to Control?

Abstract: Influenza viruses are genetically labile pathogens which avoid immune detection by constantly changing their coat proteins. Most human infections are caused by mildly pathogenic viruses which rarely cause life-threatening disease in healthy people, but some individuals with a weakened immune system can experience severe complications. Widespread infections with highly pathogenic strains of influenza virus are less common, but have the potential to cause enormous death tolls among healthy adults if infection rates reach pandemic proportions. Increased virulence has been attributed to a variety of factors, including enhanced susceptibility to coinfection with common strains of bacteria. The mechanisms that facilitate dual infection are a major focus of current research, as preventative measures are needed to avert future pandemics. ... Read more

Determination of Role of Thromboxane A2 in Rheumatoid Arthritis

Abstract: Introduction: To date, the etiology of rheumatoid arthritis (RA) remains largely unknown, and the therapies are still unsatisfactory. The biosynthesis of thromboxane A2 (TxA2) is increased in RA patients, suggesting a role of TxA2 in RA pathology. Methods: RA patients were divided into two groups, DMARDs and non-DMARDs, according to their use of disease-modifying antirheumatic drugs (DMARDs). Sera from RA patients and healthy controls were extracted and subjected to enzyme immunoassays for measurement of the thromboxane B2 (TxB2) level. The statistical correlations between serum TxB2 levels and disease activity score of 28 joints (DAS28), C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR) were calculated. Moreover, the effects of dual TxA2 modulator BM567 on cell proliferation as well as protein expression of α-actinin and NF-κB2 in RA fibroblast-like synovial (FLS) cells MH7A were determined by MTS assays and Western blot analysis, respectively. The effects of BM567 on mRNA expression of cyclooxygenase (COX)-2, a downstream product of NF-κB2 and an upstream enzyme of TxA2, was examined by real-time quantitative PCR experiments. Results: Serum TxB2 level was significantly higher in RA patients as compared to healthy controls. Both DAS28 score and serum TxB2 levels were slightly lower in the DMARDs group than the non-DMARDs group, without statistical significance, and there was positive correlation between these two factors. BM567 significantly suppressed cell proliferation as well as expression of α-actinin, NF-κB2, p52, and COX-2 in MH7A. Conclusion: TxA2 plays an important role in RA pathology, synovial cell proliferation in particular, through an auto-regulatory feedback loop. Thus, targeting TxA2 may represent a promising add-on therapy in the treatment of RA. ... Read more

Mechanisms of Autoimmune Liver Disease

Abstract: The immune system of the liver is characterized by a predominant innate component. Several innate immune cell populations have been implicated in the pathogenesis of immune-mediated hepatic diseases, which are frequently associated with systemic symptoms or with co-morbidities affecting other organ systems. Thus, next to tissue-specific factors, general tolerance mechanisms are affected in devastating hepatic disorders like primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), or primary biliary cirrhosis (PBC). The innate immune cell populations abundantly detected within the liver and endowed with potent immunomodulatory capacities include innate lymphoid cells (ILCs) and natural killer T (NKT) cells. While both ILCs and NKT cells can be activated by different cytokines and/or chemokines, NKT cells also respond to (glyco-) lipid antigens engaging their canonical, semi-invariant TCR. Once activated, ILCs and NKT cells release copious amounts of Th1, Th2, and/or Th17 cytokines that shape subsequent innate and adaptive immune responses. Those immunomodulatory features as well as the recently described antigen-presenting capacity of ILCs and/or the bi-directional functional role of NKT cells might not only underlie the pathogenic mechanisms in the respective disorders, but also provide promising targets for clinical intervention. We will discuss these novel aspects as well as the role of alarmin-like cytokines such as IL-33 in the context of ILC and NKT cell activation and the consequences for the induction and progress of hepatic tissue damage and fibrosis. ... Read more

MicroRNAs Regulate Immune System Via Multiple Targets

Abstract: MicroRNAs (miRNAs) represent the most abundant class of regulators of gene expression. Each miRNA may suppress multiple mRNA targets, while one mRNA can be targeted by many miRNAs for precise control of a wide range of cellular processes. The important role of miRNAs in the immune system is highlighted by the conditional Dicer knockout mouse, which exhibited profound aberrant development and function of immune cells. One particular miRNA, miR-155, is highly expressed and plays important role in lymphocytes. In this review we focused on the role of miRNA, especially miR-155, via their predicted and known mRNA targets in innate and adaptive immunity. Finally, we discussed the potential of miRNAs as novel targets for the diagnosis and therapy of immune system diseases. ... Read more

Advances in Pathogenesis and Treatment of ANCA-associated Vasculitis

Abstract: Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed to proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA) are sensitive and specific markers for their associated diseases, granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) and microscopic polyangiitis (MPA), respectively. Clinical observations suggest but do not prove that ANCA are involved in the pathogenesis of GPA and MPA. In vivo and in vitro experimental data strongly suggest if not prove that MPO-ANCA underlie the pathological lesions seen in MPO-ANCA associated MPA. This is less clear for PR3-ANCA associated GPA in which, besides small-vessel vasculitis, granulomatous inflammation is apparent. Here, cellular immunity appears to play an additional role. Insight into the pathogenetic events involved in these diseases has resulted in new ways of treatment that target the specific pathways that underlie the development of the lesions. ... Read more

Bimodal Plasma Metabolomics Strategy Identifies Novel Inflammatory Metabolites in Inflammatory Bowel Diseases

Abstract: Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by variable phenotypes. Metabolites are signatures of biochemical activity that can reveal unknown pathogenic pathways. We employed untargeted mass spectrometry (MS) based metabolomics to identify novel inflammatory mechanisms in IBD and a targeted assay to quantify metabolites of the auto-immunomodulating kynurenine pathway (KP) in IBDs and health. Materials and Methods: Metabolome analysis of CD, UC, and control plasmas was performed on a Liquid Chromatography (LC)-MS/MS system. KP metabolites quinolinic acid (QA) and picolinic acid (PA) were quantified by gas chromatography/MS. Results: Nineteen UC, 25 CD, and 9 control plasmas were analyzed: 34 metabolites exhibited abundance profiles associated with CD by global metabolome analysis (P≤0.05, false discovery rate q≤0.01). Notably, inflammatory-implicated metabolites angiotensin IV (P=0.049, q<0.001), diphthamide (P=0.018, q<0.001), and GM3 gangliosides (P<0.001, q<0.001) were increased in CD. By targeted kynurenine metabolites assay, QA (73.53 ng/mL ± 23.40 SD) and combined kynurenine metabolites (CKM) were increased in CD (120.19 ± 39.71) compared to controls (QA  50.14 ± 15.04; P<0.01; CKM 92.73 ± 26.30; P<0.01). CD QA positively correlated with CDAI (r=0.85; P<0.01), CRP (r=0.46; P=0.01), and ESR (r=0.42; P=0.03), while CKMs correlated with CDAI (r=0.615; P<0.01) and CRP (r=0.615; P=0.02). Conclusions: Associations of angiotensin IV, diphthamide, and GM3 gangliosides with CD implicate novel pathways in activating a Th1/Th17 inflammatory profile. Increased QA concentrations in CD may indicate a defective auto-immunomodulation mechanism. ... Read more

Interplay Between microRNAs, Toll-like Receptors, and HIV-1: Potential Implications in HIV-1 Replication and Chronic Immune Activation

Abstract: MicroRNAs (miRNAs) are important cellular, small non-coding RNAs that regulate host gene expression and have well-characterized roles in inflammation and infectious diseases. It has become apparent as well that cellular miRNAs can play crucial roles in controlling HIV-1 infection and replication. Whether HIV-1 encodes and is able to express viral miRNAs in infected cells remains controversial. HIV-1 can manipulate the biogenesis of miRNAs as well as the expression profiles of cellular miRNAs. Toll-Like receptors (TLRs) are important pathogen recognition receptors that sense invading pathogens orchestrating innate and adaptive immune responses. Innate immune recognition of HIV-1 infection leads to activation of TLR7/8. Recent evidence has shown that certain miRNAs can also be recognized by TLR7/8 leading to immune activation. However, the potential TLR7/8-mediated recognition of HIV-1 encoded miRNAs and/or cellular miRNAs modulated in HIV-1 infected cells has not been experimentally explored. In this review, we summarize the current literature on HIV-1 infection and miRNAs. Furthermore, we underscore the need for future research on potential miRNA-induced activation of TLR7/8, which might contribute to the chronic immune activation observed in HIV-1 infected patients. ... Read more

Cholesterol Crystals Induce Inflammatory Cytokines Expression in a Human Retinal Pigment Epithelium Cell Line by Activating the NF-kappaB Pathway

Abstract: Purpose: To investigate the expression of inflammatory cytokines in ARPE-19 cells after stimulation with cholesterol crystals. Methods: APRE-19 cells were cultured, primed with IL-1α, and treated with cholesterol crystals under different concentrations. Inflammatory cytokines (mature-IL-1β, IL-6, and IL-8) in supernatant and inflammatory cytokines (pro-IL-1β, IL-18) in cell lysate were detected by western blot. The NF-κB pathway inhibitor BAY 11-7082 was used to determine the pathway of cytokine expression. Results: Cholesterol crystals did not induce the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, but did increase pro-IL-1β expression in ARPE-19 cells. Cholesterol crystals increased pro-IL-1β expression by activating the NF-κB pathway. Cholesterol crystal activation of the NF-κB pathway also leads to increased IL-6 and IL-8 expression. Conclusion: Cholesterol crystals can induce inflammatory cytokine expression in ARPE-19 cells by activating the NF-κB pathway. ... Read more

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