Mediators of Inflammation The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Curcumin Attenuation of Wear Particle-Induced Osteolysis via RANKL Signaling Pathway Suppression in Mouse Calvarial Model Wed, 20 Sep 2017 06:33:30 +0000 Wear particle-induced chronic inflammation and osteoclastogenesis are two critical factors in the osteolytic process. Curcumin (CUR) is an active compound of the medicinal herb Curcuma longa and has anti-inflammatory and antiosteoclastogenic properties. Our study tested the hypothesis that CUR might attenuate polymethylmethacrylate- (PMMA-) induced inflammatory osteolysis using mouse calvaria osteolysis model in vivo and in vitro. The mice were divided into four groups: phosphate-buffered saline group, CUR, PMMA, and PMMA + CUR groups. Three days before PMMA particle implantation, the mice were intraperitoneally injected with CUR (25 mg/kg/day). Ten days after the operation, the mouse calvaria was harvested for microcomputed tomography, histomorphometry, and molecular biology analysis. As expected, CUR markedly reduced the secretion of tumor necrosis factor-α, interleukin- (IL-) 1β, and IL-6 in the calvarial organ culture. Moreover, CUR suppressed osteoclastogenesis and decreased bone resorption in vivo compared with PMMA-stimulated calvaria. Furthermore, CUR downregulated the osteoclast-specific gene expression and reversed the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin messenger RNA and protein ratio in PMMA particle-stimulated mice. These results suggest that CUR attenuated PMMA particle-induced inflammatory osteolysis by suppressing the RANKL signaling pathway in the murine calvarium, which could be a candidate compound to prevent and treat AL. Tao Cheng, Yaochao Zhao, Bin Li, Mengqi Cheng, Jiaxing Wang, and Xianlong Zhang Copyright © 2017 Tao Cheng et al. All rights reserved. Osteopontin Augments M2 Microglia Response and Separates M1- and M2-Polarized Microglial Activation in Permanent Focal Cerebral Ischemia Wed, 20 Sep 2017 05:47:31 +0000 Background. Focal cerebral ischemia induces distinct neuroinflammatory processes. We recently reported the extracellular phosphor-glyco-protein osteopontin (OPN) to directly affect primary microglia in vitro, promoting survival while shifting their inflammatory profile towards a more neutral phenotype. We here assessed the effects of OPN on microglia after stroke in vivo, with focus on infarct demarcation. Methods. Animals underwent focal photothrombotic stroke and were injected intracerebroventricularly with 500 μg OPN or vehicle. Immunohistochemistry assessed neuronal damage and infarct volume, neovascularisation, glial scar formation, microglial activation, and M1 and M2 polarisation. Results. After photothrombotic stroke, areas covered by M1 and M2 microglia substantially overlapped. OPN treatment reduced that overlap, with microglia appearing more spread out and additionally covering the infarct core. OPN additionally modulated the quantity of microglia subpopulations, reducing iNOS+ M1 cells while increasing M2 microglia, shifting the M1/M2 balance towards an M2 phenotype. Moreover, OPN polarized astrocytes towards the infarct. Conclusion. Microglial activation and M1 and M2 polarization have distinct but overlapping spatial patterns in permanent focal ischemia. Data suggest that OPN is involved in separating M1 and M2 subpopulations, as well as in shifting microglia polarization towards the M2 phenotype modulating beneficially inflammatory responses after focal infarction. Anne Ladwig, Helene Luise Walter, Jörg Hucklenbroich, Antje Willuweit, Karl-Josef Langen, Gereon Rudolph Fink, Maria Adele Rueger, and Michael Schroeter Copyright © 2017 Anne Ladwig et al. All rights reserved. Aloperine Protects Mice against DSS-Induced Colitis by PP2A-Mediated PI3K/Akt/mTOR Signaling Suppression Tue, 19 Sep 2017 07:11:13 +0000 Colitis is a major form of inflammatory bowel disease which involved mucosal immune dysfunction. Aloperine is an alkaloid isolated from the shrub Sophora alopecuroides L. and has been recognized as an effective treatment for inflammatory and allergic diseases. The present study aimed to examine the molecular mechanisms underlying aloperine-mediated colitis protection. We found that aloperine treatment improved colitis induced by dextran sodium sulfate (DSS) based on body weight, disease activity index, colonic length, and spleen index. Aloperine also effectively attenuated DSS-induced intestinal inflammation based on the pathological score and myeloperoxidase expression and activity in colon tissues. In addition, aloperine regulated T-cell proportions and promoted Foxp3 expression in the spleens and mesenteric lymph nodes of DSS-induced colitis mice and in the spleens of the Foxp3GFP mice. Aloperine inhibited Jurkat and mouse naïve T-cell apoptosis. Furthermore, aloperine inhibited PI3K/Akt/mTOR signaling and upregulated PP2A expression in the DSS-induced colitis mice and in Jurkat cells, but LB-100 (PP2A inhibitor) resulted in an elevated Akt activity in Jurkat cells, activated T-cells, and human splenic mononuclear cells. Aloperine inhibited T-cell and lymphocyte proliferation, but LB-100 reverse these effects. In conclusion, aloperine regulates inflammatory responses in colitis by inhibiting the PI3K/Akt/mTOR signaling in a PP2A-dependent manner. Xiaoxia Fu, Fei Sun, Faxi Wang, Junai Zhang, Biying Zheng, Jixin Zhong, Tiantian Yue, Xuebao Zheng, Jun-Fa Xu, and Cong-Yi Wang Copyright © 2017 Xiaoxia Fu et al. All rights reserved. Acid-Sensing Ion Channels as Potential Therapeutic Targets in Neurodegeneration and Neuroinflammation Tue, 19 Sep 2017 00:00:00 +0000 Acid-sensing ion channels (ASICs) are a family of proton-sensing channels that are voltage insensitive, cation selective (mostly permeable to Na+), and nonspecifically blocked by amiloride. Derived from 5 genes (ACCN1–5), 7 subunits have been identified, 1a, 1b, 2a, 2b, 3, 4, and 5, that are widely expressed in the peripheral and central nervous system as well as other tissues. Over the years, different studies have shown that activation of these channels is linked to various physiological and pathological processes, such as memory, learning, fear, anxiety, ischemia, and multiple sclerosis to name a few, so their potential as therapeutic targets is increasing. This review focuses on recent advances that have helped us to better understand the role played by ASICs in different pathologies related to neurodegenerative diseases, inflammatory processes, and pain. Audrey Ortega-Ramírez, Rosario Vega, and Enrique Soto Copyright © 2017 Audrey Ortega-Ramírez et al. All rights reserved. Pretreatment Liver Injury Predicts Poor Prognosis of DLBCL Patients Sun, 17 Sep 2017 00:00:00 +0000 Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphoma, with different clinical manifestation and prognosis. The International Prognostic Index (IPI), an index designed during the prerituximab era for aggressive lymphoma, showed variable values in the prediction of patient clinical outcomes. The aim of this study was to analyze the prognostic value and causes of pretreatment liver injury in 363 de novo DLBCL patients in our institution. Pretreatment liver impairment, commonly detected in lymphoma patients, showed significant association with poor outcomes and increased serum inflammatory cytokines in DLBCL patients but had no relation to hepatitis B virus replication nor lymphomatous hepatic infiltration. Multivariate analysis revealed that liver dysfunction, advanced Ann Arbor stage, and elevated lactate dehydrogenase (LDH) were independent adverse prognostic factors of both PFS and OS. Accordingly, a new liver-IPI prognostic model was designed by adding liver injury as an important factor in determining IPI score. Based on Kaplan-Meier curves for PFS and OS, the liver-IPI showed better stratification in DLBCL patients than either the IPI or the revised IPI in survival prediction. Qing Shi, Rong Shen, Chao-Fu Wang, Xing Fan, Ying Qian, Bin-Shen Ou-Yang, Yan Zhao, Christophe Leboeuf, Anne Janin, Shu Cheng, Li Wang, and Wei-Li Zhao Copyright © 2017 Qing Shi et al. All rights reserved. Middermal Elastolysis: Dermal Fibroblasts Cooperate with Inflammatory Cells to the Elastolytic Disorder Sun, 17 Sep 2017 00:00:00 +0000 Little is known about the cause and pathophysiology of middermal elastolysis (MDE). In this condition, variable inflammatory infiltrate may be present or not together with loss of elastic fibres in the middermis that spares both papillary and lower reticular dermis. MDE may be a consequence of abnormal extracellular matrix degradation related to an imbalance between elastolytic enzymes released from inflammatory and resident cells and their naturally occurring inhibitors. However, the cause of this imbalance is still an object of investigation. In order to shed light on the role of fibroblasts in MDE, we used fibroblast cultures from MDE and control subjects to evaluate matrix metalloproteinases (MMPs) and their major inhibitor TIMP-1, which in combination with neutrophil or macrophage proteases released in inflamed areas may influence the elastolytic burden. We demonstrate that fibroblasts derived from MDE produce in vitro low levels of TIMP-1, the major inhibitor of MMPs. Elevated levels of MMP-2, MMP-14, and TIMP-2 capable to activate in a cooperative manner pro-MMP-2 are present in MDE tissue samples. Additionally, significant reaction for MMP-1 is present in the same MDE areas. These data all together suggest that ECM changes in MDE are due to cooperation of different cell populations (i.e., inflammatory cells and fibroblasts). Giovanna De Cunto, Arianna Lamberti, Maria Margherita de Santi, Clelia Miracco, Michele Fimiani, Giuseppe Lungarella, and Eleonora Cavarra Copyright © 2017 Giovanna De Cunto et al. All rights reserved. Illicium verum Extract and Trans-Anethole Attenuate Ovalbumin-Induced Airway Inflammation via Enhancement of Foxp3+ Regulatory T Cells and Inhibition of Th2 Cytokines in Mice Thu, 14 Sep 2017 00:00:00 +0000 Illicium verum is used in traditional medicine to treat inflammation. The study investigates the effects of IVE and its component, trans-anethole (AET), on airway inflammation in ovalbumin- (OVA-) induced asthmatic mice. Asthma was induced in BALB/c mice by systemic sensitization to OVA, followed by intratracheal, intraperitoneal, and aerosol allergen challenges. IVE and AET were orally administered for four weeks. We investigated the effects of treatment on airway hyperresponsiveness, IgE production, pulmonary eosinophilic infiltration, immune cell phenotypes, Th2 cytokine production in bronchoalveolar lavage, Th1/Th2 cytokine production in splenocytes, forkhead box protein 3 (Foxp3) expression, and lung histology. IVE and AET ameliorated OVA-driven airway hyperresponsiveness (), pulmonary eosinophilic infiltration (), mucus hypersecretion (), and IL-4, IL-5, IL-13, and CCR3 production (), as well as IgE levels (). IVE and AET increased Foxp3 expression in lungs (). IVE and AET reduced IL-4 and increased IFN-γ production in the supernatant of splenocyte cultures (). Histological studies showed that IVE and AET inhibited eosinophilia and lymphocyte infiltration in lungs (). These results indicate that IVE and AET exert antiasthmatic effects through upregulation of Foxp3+ regulatory T cells and inhibition of Th2 cytokines, suggesting that IVE may be a potential therapeutic agent for allergic lung inflammation. Yoon-Young Sung, Seung-Hyung Kim, Dong-Seon Kim, Ji-eun Lee, and Ho Kyoung Kim Copyright © 2017 Yoon-Young Sung et al. All rights reserved. Seasonal Variation in Vitamin D in Association with Age, Inflammatory Cytokines, Anthropometric Parameters, and Lifestyle Factors in Older Adults Thu, 14 Sep 2017 00:00:00 +0000 Vitamin D deficiency is present even in sunny regions. Ageing decreases pre-vitamin D production in the skin and is associated with altered cytokine profile. We performed a multivariate analysis considering lifestyle factors, anthropometric, and inflammatory markers according to seasonal variation in Mexican healthy older adults. The same cohort was followed during 12 months. Vitamin D deficiency/insufficiency was found in 91.3% of the subjects despite living in appropriate latitude (25°40′0″N). 25(OH)D levels remained below <30 ng/mL through all seasons. Vitamin D deficiency did not correlate to sun exposure or dietary intake. Gender was the strongest associated factor, explaining a variance of 20%. Waist circumference (WC) greater than 88 cm was a risk factor for vitamin D deficiency. Age (>74 years) combined with WC (>88 cm) and BMI (>32.7) showed a high probability (90%) of vitamin D deficiency. Remarkably, an increase in one centimeter in WC decreased 25(OH)D by 0.176 ng/mL, while an increase in one point BMI decreased 25(OH)D by 0.534 ng/mL. A cutoff point of 74 years of age determined probability of vitamin D hipovitaminosis. Vitamin D deficiency was correlated with TNF-α serum levels, possibly increasing the susceptibility of older adults to a proinflammatory state and its related diseases. Leticia Elizondo-Montemayor, Elena C. Castillo, Carlos Rodríguez-López, José R. Villarreal-Calderón, Merit Gómez-Carmona, Sofia Tenorio-Martínez, Bianca Nieblas, and Gerardo García-Rivas Copyright © 2017 Leticia Elizondo-Montemayor et al. All rights reserved. Ubiquitin-Specific Protease 2 Modulates the Lipopolysaccharide-Elicited Expression of Proinflammatory Cytokines in Macrophage-like HL-60 Cells Tue, 12 Sep 2017 07:56:01 +0000 We investigated the regulatory roles of USP2 in mRNA accumulation of proinflammatory cytokines in macrophage-like cells after stimulation with a toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). Human macrophage-like HL-60 cells, mouse macrophage-like J774.1 cells, and mouse peritoneal macrophages demonstrated negative feedback to USP2 mRNA levels after LPS stimulation, suggesting that USP2 plays a significant role in LPS-stimulated macrophages. USP2 knockdown (KD) by short hairpin RNA in HL-60 cells promoted the accumulation of transcripts for 25 of 104 cytokines after LPS stimulation. In contrast, limited induction of cytokines was observed in cells forcibly expressing the longer splice variant of USP2 (USP2A), or in peritoneal macrophages isolated from Usp2a transgenic mice. An ubiquitin isopeptidase-deficient USP2A mutant failed to suppress LPS-induced cytokine expression, suggesting that protein ubiquitination contributes to USP2-mediated cytokine repression. Although USP2 deficiency did not accelerate TNF receptor-associated factor (TRAF) 6-nuclear factor-κB (NF-κB) signaling, it increased the DNA binding ratio of the octamer binding transcription factor (Oct)-1 to Oct-2 in TNF, CXCL8, CCL4, and IL6 promoters. USP2 decreased nuclear Oct-2 protein levels in addition to decreasing the polyubiquitination of Oct-1. In summary, USP2 modulates proinflammatory cytokine induction, possibly through modification of Oct proteins, in macrophages following TLR4 activation. Hiroshi Kitamura, Takeshi Ishino, Yoshinori Shimamoto, Jun Okabe, Tomomi Miyamoto, Eiki Takahashi, and Ichiro Miyoshi Copyright © 2017 Hiroshi Kitamura et al. All rights reserved. Group 2 Innate Lymphoid Cells Are Involved in Skewed Type 2 Immunity of Gastric Diseases Induced by Helicobacter pylori Infection Tue, 12 Sep 2017 00:00:00 +0000 H. pylori induces a complicated local and systematic immune response and contributes to the carcinogenesis of gastric cancer. A primary type 1 immune response is evoked by H. pylori since its occurrence. However, it is not unusual that an inhibitory immunity is dominant in H. pylori-associated diseases, which are promoted by the formation of immunosuppressive microenvironment. But whether group 2 innate lymphoid cells (ILC2s) plays a critical role in H. pylori-induced skewed type 2 immunity is still unclear. In the present study, firstly, we confirmed that type 1 immunity was inhibited and type 2 immunity were undisturbed or promoted after H. pylori infection in vitro and in vivo. Secondly, GATA-3 was firstly found to be increased in the interstitial lymphocytes from H. pylori-associated gastric cancer, among them, Lin−GATA-3+ cells and Lin+GATA-3+ cells were also found to be enhanced, which indicated an important role for ILC2s in H. pylori infection. More importantly, ILC2s were found to be increased after H. pylori infection in clinical patients and animal models. In conclusion, our results indicated that ILC2-mediated innate immune response might play a potential role in dominant type 2 phenotype and immunosuppressive microenvironment in H. pylori infection. Rong Li, Xiao-xia Jiang, Lin-fang Zhang, Xiao-ming Liu, Ting-zi Hu, Xiu-juan Xia, Ming Li, and Can-xia Xu Copyright © 2017 Rong Li et al. All rights reserved. Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα Sun, 10 Sep 2017 00:00:00 +0000 Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFα is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFα levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFα toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFα is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFα in ALS in the light of its multisystem nature. Massimo Tortarolo, Daniele Lo Coco, Pietro Veglianese, Antonio Vallarola, Maria Teresa Giordana, Gabriella Marcon, Ettore Beghi, Marco Poloni, Michael J. Strong, Anand M. Iyer, Eleonora Aronica, and Caterina Bendotti Copyright © 2017 Massimo Tortarolo et al. All rights reserved. Microglia in Health and Disease: A Double-Edged Sword Sun, 10 Sep 2017 00:00:00 +0000 Ana Raquel Santiago, Liliana Bernardino, Marta Agudo-Barriuso, and Joana Gonçalves Copyright © 2017 Ana Raquel Santiago et al. All rights reserved. Neuroinflammation and ALS: Transcriptomic Insights into Molecular Disease Mechanisms and Therapeutic Targets Thu, 07 Sep 2017 00:00:00 +0000 Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. Despite the mechanism underlying motor neuron death is not yet clarified, multiple pathogenic processes have been proposed to account for ALS. Among these, inflammatory/immune responses have recently gained particular interest, although there are conflicting reports on the role of these processes in ALS pathogenesis and treatment. This apparent discrepancy may be due to the absence of an effective stratification of ALS patients into subgroups with markedly different clinical, biological, and molecular features. Our research group recently described genome-wide characterization of motor cortex samples from sporadic ALS (SALS) patients, revealing the existence of molecular and functional heterogeneity in SALS. Here, we reexamine data coming from our previous work, focusing on transcriptomic changes of inflammatory-related genes, in order to investigate their potential contribution in ALS. A total of 1573 inflammatory genes were identified as differentially expressed between SALS patients and controls, characterizing distinct topological pathways and networks, suggestive of specific inflammatory molecular signatures for different patient subgroups. Besides providing promising insights into the intricate relationship between inflammation and ALS, this paper represents a starting point for the rationale design and development of novel and more effective diagnostic and therapeutic applications. Giovanna Morello, Antonio Gianmaria Spampinato, and Sebastiano Cavallaro Copyright © 2017 Giovanna Morello et al. All rights reserved. What is “Hyper” in the ALS Hypermetabolism? Thu, 07 Sep 2017 00:00:00 +0000 The progressive and fatal loss of upper (brain) and lower (spinal cord) motor neurons and muscle denervation concisely condenses the clinical picture of amyotrophic lateral sclerosis (ALS). Despite the multiple mechanisms believed to underlie the selective loss of motor neurons, ALS aetiology remains elusive and obscure. Likewise, there is also a cluster of alterations in ALS patients in which muscle wasting, body weight loss, eating dysfunction, and abnormal energy dissipation coexist. Defective energy metabolism characterizes the ALS progression, and such paradox of energy balance stands as a challenge for the understanding of ALS pathogenesis. The hypermetabolism in ALS will be examined from tissue-specific energy imbalance (e.g., skeletal muscle) to major energetic pathways (e.g., AMP-activated protein kinase) and whole-body energy alterations including glucose and lipid metabolism, nutrition, and potential involvement of interorgan communication. From the point of view here expressed, the hypermetabolism in ALS should be evaluated as a magnifying glass through which looking at the ALS pathogenesis is from a different perspective in which defective metabolism can disclose novel mechanistic interpretations and lines of intervention. Alberto Ferri and Roberto Coccurello Copyright © 2017 Alberto Ferri and Roberto Coccurello. All rights reserved. TWEAK/Fn14 Activation Participates in Skin Inflammation Wed, 06 Sep 2017 00:00:00 +0000 Tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) participates in multiple biological activities via binding to its sole receptor—fibroblast growth factor-inducible 14 (Fn14). The TWEAK/Fn14 signaling pathway is activated in skin inflammation and modulates the inflammatory responses of keratinocytes by activating nuclear factor-κB signals and enhancing the production of several cytokines, including interleukins, monocyte chemotactic protein-1, RANTES (regulated on activation, normal T cell expressed and secreted), and interferon gamma-induced protein 10. Mild or transient TWEAK/Fn14 activation contributes to tissular repair and regeneration while excessive or persistent TWEAK/Fn14 signals may lead to severe inflammatory infiltration and tissue damage. TWEAK also regulates cell fate of keratinocytes, involving the function of Fn14-TNF receptor-associated factor-TNF receptor axis. By recruiting inflammatory cells, promoting cytokine production, and regulating cell fate, TWEAK/Fn14 activation plays a pivotal role in the pathogenesis of various skin disorders, such as psoriasis, atopic dermatitis, cutaneous vasculitis, human papillomavirus infection and related skin tumors, and cutaneous autoimmune diseases. Therefore, the TWEAK/Fn14 pathway may be a potential target for the development of novel therapeutics for skin inflammatory diseases. Qilu Liu, Shengxiang Xiao, and Yumin Xia Copyright © 2017 Qilu Liu et al. All rights reserved. Patients with Systemic Lupus Erythematosus Show Increased Levels and Defective Function of CD69+ T Regulatory Cells Wed, 06 Sep 2017 00:00:00 +0000 T regulatory (Treg) cells have a key role in the pathogenesis of chronic inflammatory and autoimmune diseases. A CD4+CD69+ T cell subset has been described that behaves as Treg lymphocytes, exerting an important immune suppressive effect. In this study, we analyzed the levels and function of CD4+CD69+ Treg cells in patients with systemic lupus erythematosus (SLE). Blood samples were obtained from 22 patients with SLE and 25 healthy subjects. Levels of CD4+CD69+ Treg cells were analyzed by multiparametric flow cytometry, and their function was measured by an assay of suppression of lymphocyte activation and through the inhibition of cytokine synthesis. We found an increased percent of CD4+CD25varCD69+TGF-β+IL-10+Foxp3− lymphocytes in patients with SLE compared to controls. In addition, a significant diminution in the suppressive effect of these cells on the activation of autologous T lymphocytes was observed in most patients with SLE. Accordingly, CD69+ Treg cells from SLE patients showed a defective capability to inhibit the release of IL-2, IL-6, IL-10, and IL-17A by autologous lymphocytes. Our findings suggest that while CD4+CD69+ Treg lymphocyte levels are increased in SLE patients, these cells are apparently unable to contribute to the downmodulation of the autoimmune response and the tissue damage seen in this condition. Marlen Vitales-Noyola, Brenda Oceguera-Maldonado, Perla Niño-Moreno, Nubia Baltazar-Benítez, Lourdes Baranda, Esther Layseca-Espinosa, Carlos Abud-Mendoza, and Roberto González-Amaro Copyright © 2017 Marlen Vitales-Noyola et al. All rights reserved. Anti-TNF-Alpha-Adalimumab Therapy Had Time Lag of Improvement in Synovial Hypertrophy Compared to Rapid Response in Power Doppler Synovial Vascularity Wed, 06 Sep 2017 00:00:00 +0000 Objectives. The quantification of synovitis is of great significance for follow-up in patients with rheumatoid arthritis (RA). This study aimed to validate the use of power Doppler ultrasonography (PDUS) for evaluating synovial vascularity and synovial hypertrophy for synovitis in patients with rheumatoid arthritis treated with adalimumab. Materials and Methods. The synovial disease activity and vascularity of RA on both wrists (radio-carpal joint) were assessed using GS and PDUS to derive the composite US scores based on abnormal counts and severity. The relationship between each measure was determined. Results. The 71 patients who received adalimumab therapy had significantly decreased DAS28, ESR, and CRP. After one month, PD score decreased and then remained low for 12 months. Synovial hypertrophy did not change until 3–6 months after, when it started to improve (). By multivariate analysis, sex, age, BMI, and DAS28 did not lead to any difference between synovial hypertrophy and PDUS changes (). Discussion. Composite US markers of synovial hypertrophy correlate significantly to the DAS28 score and ESR/CRP in adult RA. The time needed for synovial hypertrophy to decrease may be up to 3–6 months after adalimumab therapy. Switching to biological therapy before 3–6 months is inappropriate and ineffective. Ying-Chou Chen, Chi-Hua Ko, Jia-Feng Chen, Chung-Yuan Hsu, Wen-Chan Chiu, and Tien-Tsai Cheng Copyright © 2017 Ying-Chou Chen et al. All rights reserved. Alteration of Inflammatory Mediators in the Upper and Lower Airways under Chronic Intermittent Hypoxia: Preliminary Animal Study Wed, 06 Sep 2017 00:00:00 +0000 Purpose. We hypothesized that CIH may affect the upper airway immune system and aimed to verify whether CIH can induce airway inflammation in a murine obstructive sleep apnea (OSA) model. Methods. C57BL6 male mice were exposed to intermittent hypoxia (CIH group; 5 ~ 21% FiO2, 120 sec cycles, 12 h/d, ) or room air (Sham group, ) for up to 4 weeks in identical chambers. Nasal and lung tissues and lavage fluid were collected and analyzed by multiplex assay. Lung lavage fluid was also utilized for FACS analysis to determine eosinophil count. Results. We determined the protein level of 24 different cytokines, chemokines, and inflammatory mediators. Among various cytokines, levels of IL-1α, IL-1β, IL-4, IL-6, and IL-13 were significantly elevated in nose or lung tissue from the CIH group. In addition, MCP-1 and periostin were elevated in nose and lung tissue and lavage fluid from the CIH group. Conclusions. CIH for 4 weeks altered the levels of inflammatory mediators in both the nose and lungs of mouse model. We suggest that the airway immune system may be deteriorated by CIH and allergic inflammation in the upper or lower airway could be worsened by sleep apnea. Eun Jung Lee, Woon Heo, Joo Young Kim, Hyungchul Kim, Min Jung Kang, Bo Ra Kim, Ji Hyun Kim, Do Yang Park, Chang-Hoon Kim, Joo-Heon Yoon, and Hyung-Ju Cho Copyright © 2017 Eun Jung Lee et al. All rights reserved. Mediators of Inflammation and Angiogenesis in Chronic Spontaneous Urticaria: Are They Potential Biomarkers of the Disease? Tue, 05 Sep 2017 00:00:00 +0000 In chronic spontaneous urticaria (CSU), different pathophysiological mechanisms, potentially responsible for the development of the disease, have been recently described. It is likely that the activation of skin mast cells with consequent release of histamine and other proinflammatory mediators is responsible for vasodilation in the lesional skin of CSU. However, the underlying causes of mast cell activation in the disease are largely unknown and remain to be identified. Thus, in this review, we discuss new insights in the pathogenesis of CSU, focusing on inflammation and angiogenesis. The understanding of these mechanisms will enable the identification of biomarkers useful for the diagnosis, follow-up, and management of CSU and will allow the development of novel, more specific, and patient-tailored therapies. Ilaria Puxeddu, Federico Pratesi, Domenico Ribatti, and Paola Migliorini Copyright © 2017 Ilaria Puxeddu et al. All rights reserved. Dengue Virus Induces NK Cell Activation through TRAIL Expression during Infection Tue, 05 Sep 2017 00:00:00 +0000 Dengue is an acute febrile illness with a wide spectrum of signs and symptoms ranging from mild to severe forms characterized by plasma leakage that can be fatal. NK cells are one of the main effectors in early infection and may play an important role in dengue pathogenesis. We investigated NK cell involvement during dengue infection. A higher frequency of NK cell subsets and TRAIL+NK cells was found in mild DF cases when compared to that in severe cases or healthy donors. NK activation markers such as CD107a and TLR3 were upregulated in patients’ cells compared to those in healthy donors. In addition, IL12 related to NK cell activation were upregulated in mild DF cases. In vitro PBMC culture models show that DENV-stimulated and IFNα-stimulated NK cells were able to express TRAIL, suggesting an indirect activation of cells, regarding TRAIL expression. Type I IFN receptor blockage on DENV-stimulated PBMCs showed TRAIL expression on NK cells is partially IFNα dependent. In addition, during PBMC stimulation, TRAIL expression on NK cells was inversely correlated with DENV-positive monocytes. Therefore, we observed DENV-induced activation of NK cell populations. A higher activation of NK cells would promote limited viral spread, resulting in decreased inflammatory response, contributing to protection against dengue severity. Mariana Gandini, Fabienne Petitinga-Paiva, Cíntia Ferreira Marinho, Gladys Correa, Luzia Maria De Oliveira-Pinto, Luiz José de Souza, Rivaldo Venâncio Cunha, Claire Fernandes Kubelka, and Elzinandes Leal de Azeredo Copyright © 2017 Mariana Gandini et al. All rights reserved. Low Circulating TRAIL Levels Are Associated with Increase of Resistin and Lipocalin-2/ngal Adipokines in Postmenopausal Women Tue, 05 Sep 2017 00:00:00 +0000 Objective. Tumor necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) is attracting attention for its role in the physiopathology of metabolic disease/diabetes. Evidence suggests that it might protect against metabolic abnormalities driven by obesity-induced dysregulated secretion of adipokines, but this role of TRAIL has not yet been fully established. On this basis, we aimed to investigate the potential association between TRAIL and adipokine levels in a cohort of subjects in which age/gender/hormonal interferences were excluded. Methods. Serum levels of TRAIL and a panel of adipokines were measured in postmenopausal women () stratified according to waist circumference measures as normal, overweight, or obese. The panel of adipokines included interleukin- (IL-) 6, IL-8, IL-1β, adipsin, lipocalin-2/neutrophil gelatinase-associated lipocalin (ngal), TNF-alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, hepatocyte growth factor, resistin, leptin, adiponectin, and nerve growth factor. Results. Low serum TRAIL concentration (deciles I–IV) was significantly and inversely correlated with resistin and lipocalin 2/ngal levels ( and and and , resp.). Both associations retained their statistical significance after adjustment for confounding factors, such as waist circumference and age. Conclusions. Our data indicate a link between low circulating levels of TRAIL and markers of obesity-induced diseases (resistin and lipocalin-2/ngal), highlighting a new potential axis of TRAIL functions. Veronica Tisato, Paola Secchiero, Gloria Bonaccorsi, Carlo Bergamini, Pantaleo Greco, Giorgio Zauli, and Carlo Cervellati Copyright © 2017 Veronica Tisato et al. All rights reserved. SUMO E3 Ligase PIASy Mediates High Glucose-Induced Activation of NF-κB Inflammatory Signaling in Rat Mesangial Cells Tue, 05 Sep 2017 00:00:00 +0000 Background. Sumoylation is extensively involved in the regulation of NF-κB signaling. PIASy, as a SUMO E3 ligase, has been proved to mediate sumoylation of IκB kinase γ (IKKγ) and contribute to the activation of NF-κB under genotoxic agent stimulation. However, the association of PIASy and NF-κB signaling in the pathogenesis of diabetic nephropathy (DN) has not been defined. Methods. Rat glomerular mesangial cells (GMCs) were stimulated by high glucose; siRNA was constructed to silence the expression of PIASy; the expression of PIASy, SUMO isoforms (SUMO1, SUMO2/3), and NF-κB signaling components was analyzed by Western blot; the interaction between IKKγ and SUMO proteins was detected by coimmunoprecipitation; and the release of inflammatory cytokines MCP-1 and IL-6 was assayed by ELISA. Results. High glucose significantly upregulated the expression of PIASy, SUMO1, and SUMO2/3 in a dose- and time-dependent manner (), induced the phosphorylation and sumoylation of IKKγ (), and then triggered NF-κB signaling whereas MCP-1 and IL-6 were released from GMCs (). Moreover, these high glucose-induced effects were observably reversed by siRNA-mediated knockdown of PIASy (). Conclusion. The SUMO E3 ligase PIASy mediates high glucose-induced activation of NF-κB inflammatory signaling, suggesting that PIASy may be a potential therapeutic target of DN. Wei Huang, Yaling Liang, Jianhua Dong, Luping Zhou, Chenlin Gao, Chunxia Jiang, Meijuan Chen, Yang Long, and Yong Xu Copyright © 2017 Wei Huang et al. All rights reserved. Liver Regeneration: Analysis of the Main Relevant Signaling Molecules Wed, 30 Aug 2017 09:29:41 +0000 Liver regeneration is a highly organized tissue regrowth process and is the most important reaction of the liver to injury. The overall process of liver regeneration includes three phases: priming stage, proliferative phase, and termination phase. The initial step aims to induce hepatocytes to be sensitive to growth factors with the aid of some cytokines, including TNF-α and IL-6. The proliferation phase promotes hepatocytes to re-enter G1 with the stimulation of growth factors. While during the termination stage, hepatocytes will discontinue to proliferate to maintain normal liver mass and function. Except for cytokine- and growth factor-mediated pathways involved in regulating liver regeneration, new substances and technologies emerge to influence the regenerative process. Here, we reviewed novel and important signaling molecules involved in the process of liver regeneration to provide a cue for further research. Yachao Tao, Menglan Wang, Enqiang Chen, and Hong Tang Copyright © 2017 Yachao Tao et al. All rights reserved. Neutrophil Extracellular DNA Traps Induce Autoantigen Production by Airway Epithelial Cells Wed, 30 Aug 2017 00:00:00 +0000 The hypothesis of autoimmune involvement in asthma has received much recent interest. Autoantibodies, such as anti-cytokeratin (CK) 18, anti-CK19, and anti-α-enolase antibodies, react with self-antigens and are found at high levels in the sera of patients with severe asthma (SA). However, the mechanisms underlying autoantibody production in SA have not been fully determined. The present study was conducted to demonstrate that neutrophil extracellular DNA traps (NETs), cytotoxic molecules released from neutrophils, are a key player in the stimulation of airway epithelial cells (AECs) to produce autoantigens. This study showed that NETs significantly increased the intracellular expression of tissue transglutaminase (tTG) but did not affect that of CK18 in AECs. NETs induced the extracellular release of both tTG and CK18 in a concentration-dependent manner. Moreover, NETs directly degraded intracellular α-enolase into small fragments. However, antibodies against neutrophil elastase (NE) or myeloperoxidase (MPO) attenuated the effects of NETs on AECs. Furthermore, each NET isolated from healthy controls (HC), nonsevere asthma (NSA), and SA had different characteristics. Taken together, these findings suggest that AECs exposed to NETs may exhibit higher autoantigen production, especially in SA. Therefore, targeting of NETs may represent a new therapy for neutrophilic asthma with a high level of autoantigens. Youngwoo Choi, Le Duy Pham, Dong-Hyun Lee, Ga-Young Ban, Ji-Ho Lee, Seung-Hyun Kim, and Hae-Sim Park Copyright © 2017 Youngwoo Choi et al. All rights reserved. Amelioration of Ethanol-Induced Hepatitis by Magnesium Isoglycyrrhizinate through Inhibition of Neutrophil Cell Infiltration and Oxidative Damage Tue, 29 Aug 2017 08:42:36 +0000 Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. There is no effective treatment to prevent the disease progression. Magnesium isoglycyrrhizinate (MgIG) showed potent anti-inflammatory, antioxidant, and hepatoprotective activities and was used for treating liver diseases in Asia. In this study, we examined whether MgIG could protect mice against alcohol-induced liver injury. The newly developed chronic plus binge ethanol feeding model was used to study the role of MgIG in ALD. Serum liver enzyme levels, H&E staining, immunohistochemical staining, flow cytometric analysis, and real-time PCR were used to evaluate the liver injury and inflammation. We showed that MgIG markedly ameliorated chronic plus binge ethanol feeding liver injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and reduced neutrophil infiltration. The reason may be attributed to the reduced expression of proinflammatory cytokines and chemokines with the treatment of MgIG. The hepatoprotective effect of MgIG was associated with suppression of neutrophil ROS production as well as hepatocellular oxidative stress. MgIG may play a critical role in protecting against chronic plus binge ethanol feeding-induced liver injury by regulating neutrophil activity and hepatic oxidative stress. Yan Wang, Zhenzhen Zhang, Xia Wang, Dan Qi, Aijuan Qu, and Guiqiang Wang Copyright © 2017 Yan Wang et al. All rights reserved. Modulation of Dendritic Cell Apoptosis and CD8+ Cytotoxicity by Histamine: Role of Protein Kinase C Tue, 29 Aug 2017 07:17:14 +0000 Dendritic cells (DC) are able to present extracellular antigens associated with the molecules of the major histocompatibility complex class I. In a previous work, we demonstrated that the histamine (HIS), acting through H1/H4 receptors, increases the cross-presentation of soluble ovalbumin by murine DC and can enhance the recruitment of specific CD8+ T lymphocytes during the development of chronic inflammatory responses. Here, we studied in more depth the mechanisms underlying this enhancement. We showed that the cytotoxicity of specific CD8+ lymphocytes is increased in HIS-treated DC and it is lost by inhibition of vacuolar-ATPase that prevents endosome acidification. It is known that HIS acts through G protein-coupled receptors. The H1/H4 receptors are associated with a Gq subunit, which involves PKC signaling, a pathway related to the apoptotic process. Interestingly, we demonstrated for the first time that HIS prevents DC apoptosis induced by heat shock through the inhibition of caspase-3, a mechanism dependent on PKC activation, since it is reversed by its inhibition. By contrast, cytolytic activity of T lymphocytes induced by HIS-stimulated DC was independent of PKC pathway. Julieta Alcain, Enrique Podaza, María Soledad Gori, Gabriela Salamone, and Mónica Vermeulen Copyright © 2017 Julieta Alcain et al. All rights reserved. Psoriasis and Cardiovascular Risk—Do Promising New Biomarkers Have Clinical Impact? Tue, 29 Aug 2017 06:27:27 +0000 Epidemiological studies suggest an increased prevalence of cardiovascular disease (CVD) in patients with psoriasis (PS). Therefore, emphasis has lately been laid on the necessity for clinical evaluation of the risk of CVD in these patients. The systemic inflammatory markers C-reactive protein (CRP) and interleukin- (IL-) 6, which have long been used to predict future CVD in the general population, are increased manyfold in patients with PS. Lipid abnormalities characterized by elevated triglycerides, low HDL cholesterol, and higher concentrations of LDL cholesterol and its oxidized form are also prevalent in patients. There is a need for additional laboratory markers for the assessment of cardiovascular status of patients with PS. Due to frequent comorbid overweight and obesity, biologically active compounds produced by adipocytes may have an impact on monitoring the status of the cardiovascular system of patients with PS. For this purpose, two adipokines, adiponectin and leptin, have been most extensively studied. The review focuses on some inflammatory and oxidative stress aspects in patients with PS through the analysis of the impact of prominent adipokines and oxidized low-density lipoprotein (oxLDL) to assess their eligibility for clinical practice as markers of CVD risk in patients with PS. Sirje Kaur, Külli Kingo, and Mihkel Zilmer Copyright © 2017 Sirje Kaur et al. All rights reserved. Effect of IRAK-M on Airway Inflammation Induced by Cigarette Smoking Tue, 29 Aug 2017 00:00:00 +0000 Background. IRAK-M, negatively regulating Toll-like receptor, is shown the dual properties in the varied disease contexts. We studied the effect of IRAK-M deficiency on cigarette smoking- (CS-) induced airway inflammation under acute or subacute conditions in a mouse model. Methods. A number of cellular and molecular techniques were used to detect the differences between IRAK-M knockout (KO) and wild type (WT) mice exposed to 3-day or 7-week CS. Results. Airway inflammation was comparable between IRAK-M KO and WT mice under 3-day CS exposure. Upon short-term CS exposure and lipopolysaccharide (LPS) inhalation, IRAK-M KO mice demonstrated worse airway inflammation, significantly higher percentage of Th17 cells and concentrations of proinflammatory cytokines in the lungs, and significantly elevated expression of costimulatory molecules CD40 and CD86 by lung dendritic cells (DCs) or macrophages. Conversely, 7-week CS exposed IRAK-M KO mice demonstrated significantly attenuated airway inflammation, significantly lower concentrations of proinflammatory cytokines in the lungs, significantly increased percentage of Tregs, and lower expression of CD11b and CD86 by lung DCs or macrophages. Conclusions. IRAK-M plays distinctive effect on CS-induced airway inflammation, and influences Treg/Th17 balance and expression of costimulatory molecules by DCs and macrophages, depending on duration and intensity of stimulus. Haihong Gong, Tao Liu, Wei Chen, Weixun Zhou, and Jinming Gao Copyright © 2017 Haihong Gong et al. All rights reserved. Role of the Cysteinyl Leukotrienes in the Pathogenesis and Progression of Cardiovascular Diseases Mon, 28 Aug 2017 05:27:08 +0000 Cysteinyl leukotrienes (CysLTs) are potent lipid inflammatory mediators synthesized from arachidonic acid, through the 5-lipoxygenase (5-LO) pathway. Owing to their properties, CysLTs play a crucial role in the pathogenesis of inflammation; therefore, CysLT modifiers as synthesis inhibitors or receptor antagonists, central in asthma management, may become a potential target for the treatment of other inflammatory diseases such as the cardiovascular disorders. 5-LO pathway activation and increased expression of its mediators and receptors are found in cardiovascular diseases. Moreover, the cardioprotective effects observed by using CysLT modifiers are promising and contribute to elucidate the link between CysLTs and cardiovascular disease. The aim of this review is to summarize the state of present research about the role of the CysLTs in the pathogenesis and progression of atherosclerosis and myocardial infarction. Francesca Colazzo, Paolo Gelosa, Elena Tremoli, Luigi Sironi, and Laura Castiglioni Copyright © 2017 Francesca Colazzo et al. All rights reserved. Chitinase-3-Like Protein 1 (YKL-40) Is a New Biomarker of Inflammation in Psoriasis Mon, 28 Aug 2017 04:57:23 +0000 Purpose. The evaluation of new inflammatory biomarkers in psoriasis could determine therapeutic decisions. Chitinase-3-like protein 1 (YKL-40) plays a role in inflammation. The study was undertaken to check whether YKL-40 is a reliable biomarker of inflammation in psoriasis. Materials and Methods. 55 psoriatic patients were enrolled, including 21 men and 34 women, aged from 18 to 88 years. The PASI and body surface area were calculated for all patients. Blood samples were taken to evaluate serum concentration of YKL-40, as well as other inflammatory parameters, including CRP, ESR, white blood cell count, and neutrophil count. The measurements of YKL-40 level were performed by enzyme-linked immunosorbent assay (ELISA). Results. YKL-40 serum concentration was significantly higher in psoriatic patients than in the control group. No correlations were found between YKL-40 levels and other clinical or laboratory parameters. Serum YKL-40 level was elevated in 81.8% patients, whereas CRP and WBC in 20% and 7.3% of patients, respectively. Conclusions. YKL-40 could be considered as a useful biomarker of inflammation in psoriasis and is more sensitive than CRP or WBC. Increased YKL-40 may indicate psoriatic patients with a higher level of systemic inflammation, which may determine disease management. Joanna Salomon, Łukasz Matusiak, Danuta Nowicka-Suszko, and Jacek C. Szepietowski Copyright © 2017 Joanna Salomon et al. All rights reserved.