Mediators of Inflammation http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Short-Term Reproducibility of the Inflammatory Phenotype in Different Subgroups of Adult Asthma Cohort Wed, 04 Mar 2015 07:15:54 +0000 http://www.hindawi.com/journals/mi/2015/419039/ Inflammatory phenotype classification using induced sputum appears attractive as it can be applied to inflammation-based management of the patients with asthma. The aim of the study was to determine the reproducibility of inflammatory phenotype over time in patients with asthma. In 66 adults asthma was categorized as steroid-naïve (SN, ), mild to moderate (MMA, ), and refractory treated with oral corticosteroids (RA, ). Clinical assessment, skin prick testing, spirometry, and two sputum inductions in 4–6-week interval were done. Inflammatory phenotypes were classified as eosinophilic (EA), consisting of eosinophilic and mixed granulocytic phenotypes, and noneosinophilic (NEA) consisting of paucigranulocytic and neutrophilic phenotypes. During study asthma treatment remained constant. In SN group 25% of patients changed phenotype from EA to NEA and 44% changed phenotype from NEA to EA. In MMA group 26% of patients changed phenotype from EA to NEA and 50% changed phenotype from NEA to EA. In 29% of RA patients inflammatory phenotype changed from EA to NEA and in 22% it changed from NEA to EA. Inflammatory classification, using induced sputum, is not fully reproducible in adults with asthma in short-term evaluation. EA seems to be more stable phenotype across all subgroups whereas NEA remained stable only in RA group. Sebastian Majewski, Maciej Ciebiada, Mateusz Domagala, Zofia Kurmanowska, and Pawel Gorski Copyright © 2015 Sebastian Majewski et al. All rights reserved. The Role of Innate Immunity Receptors in the Pathogenesis of Inflammatory Bowel Disease Wed, 04 Mar 2015 06:58:05 +0000 http://www.hindawi.com/journals/mi/2015/936193/ Innate immunity constitutes the first line of defense, fundamental for the recognition and the initiation of an inflammatory response against microorganisms. The innate immune response relies on the sensing of microbial-associated molecular patterns through specialized structures such as toll-like receptors (TLRs) and the nucleotide oligomerization domain- (NOD-) like receptors (NLRs). In the gut, these tasks are performed by the epithelial barrier and the presence of adaptive and innate immune mechanisms. TLRs and NLRs are distributed throughout the gastrointestinal mucosa, being more expressed in the epithelium, and in lamina propria immune and nonimmune cells. These innate immunity receptors exhibit complementary biological functions, with evidence for pathways overlapping. However, as tolerance is the predominant physiological response in the gastrointestinal mucosa, it appears that the TLRs are relatively downregulated, while NLRs play a critical role in mucosal defense in the gut. Over the past two decades, genetic polymorphisms have been associated with several diseases including inflammatory bowel disease. Special emphasis has been given to the susceptibility to Crohn’s disease, in association with abnormalities in the NOD2 and in the NLRP3/inflammasome. Nevertheless, the mechanisms underlying innate immune receptors dysfunction that result in the persistent inflammation in inflammatory bowel disease remain to be clarified. Paula Peruzzi Elia, Yolanda Faia M. Tolentino, Claudio Bernardazzi, and Heitor Siffert Pereira de Souza Copyright © 2015 Paula Peruzzi Elia et al. All rights reserved. Helicobacter pylori Outer Membrane Vesicle Proteins Induce Human Eosinophil Degranulation via a β2 Integrin CD11/CD18- and ICAM-1-Dependent Mechanism Wed, 04 Mar 2015 06:54:04 +0000 http://www.hindawi.com/journals/mi/2015/301716/ Eosinophil cationic protein (ECP), a cytotoxic protein contained in eosinophils granules, can contribute to various inflammatory responses. Although Helicobacter pylori infection increases infiltration of eosinophils, the mechanisms of eosinophil degranulation by H. pylori infection are largely unknown. The goal of this study was to investigate the role of H. pylori outer membrane vesicles (OMVs) in modulating eosinophil degranulation. We found that eosinophils treated with H. pylori OMVs released significantly more ECP compared with untreated controls. In addition, eosinophils cocultured with OMV-preexposed primary gastric epithelial cells exhibited significantly increased ECP release. Similarly, eosinophils cocultured with culture supernatant (CM) from primary gastric epithelial cells exposed to OMVs (OMV-CM) released significantly higher amounts of ECP compared with eosinophils cocultured with CM from unexposed control cells. Furthermore, OMVs and OMV-CM both induced the upregulation of ICAM-1 on gastric epithelial cells and β2 integrin CD11b on eosinophils. In addition, both transduction of ICAM-1 shRNA into gastric epithelial cells and treatment with neutralizing mAbs to CD18 significantly decreased OMV-mediated or OMV-CM-mediated release of ECP. These results suggest that the eosinophil degranulation response to H. pylori OMVs occurs via a mechanism that is dependent on both β2 integrin CD11/CD18 and ICAM-1. Su Hyuk Ko, Jong Ik Jeon, Young-Jeon Kim, Ho Joo Yoon, Hyeyoung Kim, Nayoung Kim, Joo Sung Kim, and Jung Mogg Kim Copyright © 2015 Su Hyuk Ko et al. All rights reserved. Clinical Features and Genetic Background of the Periodic Fever Syndrome with Aphthous Stomatitis, Pharyngitis, and Adenitis: A Single Center Longitudinal Study of 81 Patients Wed, 04 Mar 2015 06:11:56 +0000 http://www.hindawi.com/journals/mi/2015/293417/ PFAPA syndrome is the most common autoinflammatory disorder in childhood with unknown etiology. The aim of our study was clinical evaluation of PFAPA patients from a single tertiary care center and to determine whether variations of AIM2, MEFV, NLRP3, and MVK genes are involved in PFAPA pathogenesis. Clinical and laboratory data of consecutive patients with PFAPA syndrome followed up at the University Children’s Hospital, Ljubljana, were collected from 2008 to 2014. All four genes were PCR amplified and directly sequenced. Eighty-one patients fulfilled criteria for PFAPA syndrome, 50 (63%) boys and 31 (37%) girls, with mean age at disease onset of 2.1 ± 1.5 years. Adenitis, pharyngitis, and aphthae were present in 94%, 98%, and 56%, respectively. Family history of recurrent fevers in childhood was positive in 78%. Nineteen variants were found in 17/62 (27%) patients, 4 different variants in NLRP3 gene in 13 patients, and 6 different variants in MEFV gene in 5 patients, and 2 patients had 2 different variants. No variants of clinical significance were found in MVK and AIM2 genes. Our data suggest that PFAPA could be the result of multiple low-penetrant variants in different genes in combination with epigenetic and environmental factors leading to uniform clinical picture. Daša Perko, Maruša Debeljak, Nataša Toplak, and Tadej Avčin Copyright © 2015 Daša Perko et al. All rights reserved. Protective Effects of N-Acetylcysteine in Concanavalin A-Induced Hepatitis in Mice Mon, 02 Mar 2015 11:54:50 +0000 http://www.hindawi.com/journals/mi/2015/189785/ This study was designed to study the protective effects and mechanisms of N-acetylcysteine (NAC) in concanavalin A-induced hepatitis in mice. In this study, pretreatment with NAC ameliorated the histopathological changes and suppressed inflammatory cytokines in ConA-induced hepatitis. The expression of IL-2, IL-6, TNF-α, and IFN-γ was significantly reduced in the NAC-treated groups. NAC activated PI3K/Akt pathway and inhibited the activation of NF-κB. Additionally, NAC reduced autophagosome formation, as assessed by detecting the expression of LC3 and Beclin 1. Our results demonstrate that NAC can alleviate ConA-induced hepatitis by regulating the PI3K/Akt pathway and reducing the late stages of autophagy. Our results described a new pharmaceutical to provide more effective therapies for immune hepatitis. Chengfen Wang, Yujing Xia, Yuanyuan Zheng, Weiqi Dai, Fan Wang, Kan Chen, Jingjing Li, Sainan Li, Rong Zhu, Jing Yang, Qin Yin, Huawei Zhang, Junshan Wang, Jie Lu, Yingqun Zhou, and Chuanyong Guo Copyright © 2015 Chengfen Wang et al. All rights reserved. Pathogenic Roles of Macrophage Migration Inhibitory Factor during Dengue Virus Infection Mon, 02 Mar 2015 08:41:08 +0000 http://www.hindawi.com/journals/mi/2015/547094/ Dengue virus (DENV) infection is the most common cause of viral hemorrhagic fever, which can lead to life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Hemorrhage and plasma leakage are two major hallmarks of DHF/DSS. Because the mechanisms causing these pathogenic changes are unclear, there is no effective therapy against DHF/DSS. In this review, we focus on the possible pathogenic effects of a pleiotropic cytokine, macrophage migration inhibitory factor (MIF), on the pathogenesis of DENV infection. MIF is a critical mediator of the host immune response and inflammation, and there is a correlation between the serum levels of MIF and disease severity in dengue patients. Furthermore, MIF knock-out mice exhibit less severe clinical disease and lethality. However, the role of MIF in the pathogenesis of DHF/DSS is not limited to immune cell recruitment. Recent evidence indicates that DENV infection induced MIF production and may contribute to vascular hyperpermeability and viral replication during DENV infection. The expression of both adhesion and coagulation molecules on MIF-stimulated monocytes and endothelial cells is also increased, which may contribute to inflammatory and anticoagulatory states during DHF/DSS. Therefore, blocking MIF production or its function may provide a solution for the treatment and prevention of DHF/DSS. Yung-Chun Chuang, Hong-Ru Chen, and Trai-Ming Yeh Copyright © 2015 Yung-Chun Chuang et al. All rights reserved. Purinergic Signalling in Immune System Regulation in Health and Disease Sun, 01 Mar 2015 08:43:09 +0000 http://www.hindawi.com/journals/mi/2015/106863/ Mireia Martín-Satué, Jean Sévigny, and Jesús Pintor Copyright © 2015 Mireia Martín-Satué et al. All rights reserved. Epigenetic Regulation of Inflammatory Cytokines and Associated Genes in Human Malignancies Sun, 01 Mar 2015 06:47:25 +0000 http://www.hindawi.com/journals/mi/2015/201703/ Inflammation is a multifaceted defense response of immune system against infection. Chronic inflammation has been implicated as an imminent threat for major human malignancies and is directly linked to various steps involved in tumorigenesis. Inflammatory cytokines, interleukins, interferons, transforming growth factors, chemokines, and adhesion molecules have been associated with chronic inflammation. Numerous cytokines are reported to be aberrantly regulated by different epigenetic mechanisms like DNA methylation and histone modifications in tumor tissues, contributing to pathogenesis of tumor in multiple ways. Some of these cytokines also work as epigenetic regulators of other crucial genes in tumor biology, either directly or indirectly. Such regulations are reported in lung, breast, cervical, gastric, colorectal, pancreatic, prostate, and head and neck cancers. Epigenetics of inflammatory mediators in cancer is currently subject of extensive research. These investigations may help in understanding cancer biology and to develop effective therapeutic strategies. The purpose of this paper is to have a brief view of the aberrant regulation of inflammatory cytokines in human malignancies. Rehana Yasmin, Sami Siraj, Amjad Hassan, Abdul Rehman Khan, Rashda Abbasi, and Nafees Ahmad Copyright © 2015 Rehana Yasmin et al. All rights reserved. Cardiac Migration of Endogenous Mesenchymal Stromal Cells in Patients with Inflammatory Cardiomyopathy Sat, 28 Feb 2015 10:16:41 +0000 http://www.hindawi.com/journals/mi/2015/308185/ Introduction. Mesenchymal stromal cells (MSC) have immunomodulatory features. The aim of this study was to investigate the migration and homing potential of endogenous circulating MSC in virus negative inflammatory cardiomyopathy (CMi). Methods. In 29 patients with or without CMi undergoing endomyocardial biopsies (EMB), transcardiac gradients (TCGs) of circulating MSC were measured by flow cytometry from blood simultaneously sampled from aorta and coronary sinus. The presence of MSC in EMB, cardiac inflammation, and SDF-1α mRNA expression were detected via immunohistochemistry and real-time PCR. Results. MSC defined as CD45−CD34−CD11b−CD73+CD90+ cells accounted for 0.010 [0.0025–0.048]%/peripheral mononuclear cell (PMNC) and as CD45−CD34−CD11b−CD73+CD105+ cells for 0.019 [0.0026–0.067]%/PMNC, both with similar counts in patients with or without cardiac inflammation. There was a 29.9% transcardiac reduction of circulating MSC in patients with CMi, correlating with the extent of cardiac inflammation (, multivariate analysis). A strong correlation was found between the TCG of circulating MSC and numbers of MSC (CD45−CD34−CD90+CD105+) in EMB (, ). SDF-1α was the strongest predictor for increased MSC in EMB (, multivariate analysis). Conclusions. Endogenous MSC continuously migrate to the heart in patients with CMi triggered by cardiac inflammation. Caroline Schmidt-Lucke, Felicitas Escher, Sophie Van Linthout, Uwe Kühl, Kapka Miteva, Jochen Ringe, Thomas Zobel, Heinz-Peter Schultheiss, and Carsten Tschöpe Copyright © 2015 Caroline Schmidt-Lucke et al. All rights reserved. The Chaperone Balance Hypothesis: The Importance of the Extracellular to Intracellular HSP70 Ratio to Inflammation-Driven Type 2 Diabetes, the Effect of Exercise, and the Implications for Clinical Management Thu, 26 Feb 2015 12:26:29 +0000 http://www.hindawi.com/journals/mi/2015/249205/ Recent evidence shows divergence between the concentrations of extracellular 70 kDa heat shock protein [eHSP70] and its intracellular concentrations [iHSP70] in people with type 2 diabetes (T2DM). A vital aspect regarding HSP70 physiology is its versatility to induce antagonistic actions, depending on the location of the protein. For example, iHSP70 exerts a powerful anti-inflammatory effect, while eHSP70 activates proinflammatory pathways. Increased eHSP70 is associated with inflammatory and oxidative stress conditions, whereas decreased iHSP70 levels are related to insulin resistance in skeletal muscle. Serum eHSP70 concentrations are positively correlated with markers of inflammation, such as C-reactive protein, monocyte count, and TNF-α, while strategies to enhance iHSP70 (e.g., heat treatment, chemical HSP70 inducers or coinducers, and physical exercise) are capable of reducing the inflammatory profile and the insulin resistance state. Here, we present recent findings suggesting that imbalances in the HSP70 status, described by the [eHSP70]/[iHSP70] ratio, may be determinant to trigger a chronic proinflammatory state that leads to insulin resistance and T2DM development. This led us to hypothesize that changes in this ratio value could be used as a biomarker for the management of the inflammatory response in insulin resistance and diabetes. Mauricio Krause, Thiago Gomes Heck, Aline Bittencourt, Sofia Pizzato Scomazzon, Philip Newsholme, Rui Curi, and Paulo Ivo Homem de Bittencourt Jr. Copyright © 2015 Mauricio Krause et al. All rights reserved. Inflammasome in Platelets: Allying Coagulation and Inflammation in Infectious and Sterile Diseases? Thu, 26 Feb 2015 11:42:50 +0000 http://www.hindawi.com/journals/mi/2015/435783/ Platelets are crucial effector cells in hemostasis. In addition, platelets are increasingly recognized as major inflammatory cells with key roles in innate and adaptive immune responses. Activated platelets have key thromboinflammatory activities linking coagulation to inflammatory response in a variety of coagulation disorders and vasculopathies. Recently identified inflammatory activities of platelets include the synthesis of IL-1β from spliced pre-RNA, as well as the presence and assembly of inflammasome which intermediate IL-1β secretion. Here we review the mechanisms by which platelets activate translation machinery and inflammasome assembly to synthesize and release IL-1β. The contributions of these processes to protective and pathogenic responses during infectious and inflammatory diseases are discussed. Eugenio D. Hottz, Ana Paula T. Monteiro, Fernando A. Bozza, and Patrícia T. Bozza Copyright © 2015 Eugenio D. Hottz et al. All rights reserved. Secretion of One Adipokine Nampt/Visfatin Suppresses the Inflammatory Stress-Induced NF-κB Activity and Affects Nampt-Dependent Cell Viability in Huh-7 Cells Thu, 26 Feb 2015 10:40:03 +0000 http://www.hindawi.com/journals/mi/2015/392471/ Nampt/visfatin acts in both intracellular and extracellular compartments to regulate multiple biological roles, including NAD metabolism, cancer, inflammation, and senescence. However, its function in chronic inflammation and carcinogenesis in hepatocellular carcinoma (HCC) has not been well-defined. Here we use Huh-7 hepatoma cells as a model to determine how Nampt/visfatin affects cellular survival under oxidative stress. We found that the transition of Nampt/visfatin from intracellular into extracellular form was induced by H2O2 treatment in 293T cells and confirmed that this phenomenon was not due to cell death but through the secretion of Nampt/visfatin. In addition, Nampt/visfatin suppressed cell viability in oxidative treatment in Huh-7 cells and acted on the inhibition of hepatoma cell growth. Oxidative stress also reduced the Nampt-mediated activation of NF-κB gene expression. In this study, we identify a novel feature of Nampt/visfatin which functions as an adipokine that can be secreted upon cellular stress. Our results provide an example to understand how adipokine interacts with chemotherapeutic treatment by oxidative stress in HCC. Yi-Ching Lin, Hui-Chung Wu, Chen-Chung Liao, Yi-Chih Chou, Shwu-Fen Pan, and Chi-Ming Chiu Copyright © 2015 Yi-Ching Lin et al. All rights reserved. Effect of TLR4/MyD88 Signaling Pathway on Expression of IL-1 and TNF- in Synovial Fibroblasts from Temporomandibular Joint Exposed to Lipopolysaccharide Tue, 24 Feb 2015 06:57:59 +0000 http://www.hindawi.com/journals/mi/2015/329405/ Accumulating evidence from previous studies suggested that interleukin-1 (IL-1β) and tumor necrosis factor-α (TNF-α) play an important role in pathogenesis of temporomandibular disorders (TMD). However, the cell surface receptors and the intracellular signal pathways leading to these cytokines expression are not fully understood. In the current study, we investigated the roles of Toll-like receptor 4 (TLR4) and its adaptor myeloid differentiation factor 88 (MyD88) in the expression of IL-1β and TNF-α in synovial fibroblasts (SFs) separated from rat temporomandibular joint (TMJ) with lipopolysaccharide (LPS) stimulation. The results showed that treatment with LPS could increase TLR4, MyD88, IL-1β, and TNF-α expression at both mRNA and protein levels. In addition, increased expression of IL-1β and TNF-α could be blocked by treatment with TAK-242, a blocker of TLR4 signaling, and also by MyD88 inhibitory peptide (MIP). These findings suggested that maybe TLR4/MyD88 signal transduction pathway participates in enhanced expression of IL-1 and TNF-α in patients with TMD. The activation of TLR4/MyD88 signal transduction pathway which results in production of proinflammatory factors may play a role in the pathogenesis of TMD. Xuefen Lin, Jingjing Kong, Qingting Wu, Yingying Yang, and Ping Ji Copyright © 2015 Xuefen Lin et al. All rights reserved. Increased Levels of Soluble ST2 in Patients with Active Newly Diagnosed ANCA-Associated Vasculitis Mon, 23 Feb 2015 12:31:20 +0000 http://www.hindawi.com/journals/mi/2015/603750/ Objective. ST2, a member of the interleukin-1 receptor family, is selectively expressed on Th2 cells and mediates important Th2 functions. IL-33 is a specific ligand of ST2. The aim of the study was to determine whether serum levels of soluble ST2 (sST2) or IL-33 predict activity of the disease in patients with ANCA-associated vasculitides (AAV). Methods. 139 AAV patients and 62 controls were studied. IL-33 and sST2 in the blood were measured with a commercially available ELISA. Results. Newly diagnosed AAV patients had higher sST2 levels than controls (). Levels of sST2 were significantly higher in active newly diagnosed AAV patients than in patients with remission (). IL-33 levels were higher in AAV patients than in the control groups (). However, serum IL-33 levels were not increased in patients with active AAV compared to patients in remission. IL-33 levels were higher in patients with granulomatosis with polyangiitis than in patients with microscopic polyangiitis (). Conclusions. Serum sST2, but not serum IL-33, may be a marker of activity in AAV patients. Z. Hladinova, Z. Hruskova, B. Svobodova, K. Malickova, V. Lanska, P. Konopásek, E. Jancova, R. Rysava, C. L. Edelstein, and V. Tesar Copyright © 2015 Z. Hladinova et al. All rights reserved. Response to: Comment on “Serum Amyloid A as a Marker of Persistent Inflammation and an Indicator of Cardiovascular and Renal Involvement in Patients with Rheumatoid Arthritis” Mon, 23 Feb 2015 06:27:47 +0000 http://www.hindawi.com/journals/mi/2015/749565/ Bożena Targońska-Stępniak and Maria Majdan Copyright © 2015 Bożena Targońska-Stępniak and Maria Majdan. All rights reserved. Altered Viral Replication and Cell Responses by Inserting MicroRNA Recognition Element into PB1 in Pandemic Influenza A Virus (H1N1) 2009 Thu, 19 Feb 2015 08:16:36 +0000 http://www.hindawi.com/journals/mi/2015/976575/ Objective. MicroRNAs (miRNAs) are endogenous noncoding RNAs that spatiotemporally modulate mRNAs in a posttranscriptional manner. Engineering mutant viruses by inserting cell-specific miRNA recognition element (MRE) into viral genome may alter viral infectivity and host responses in vital tissues and organs infected with pandemic influenza A virus (H1N1) 2009 (H1N1pdm). Methods. In this study, we employed reverse genetics approach to generate a recombinant H1N1pdm with a cell-specific miRNA target sequence inserted into its PB1 genomic segment to investigate whether miRNAs are able to suppress H1N1pdm replication. We inserted an MRE of microRNA-let-7b (miR-let-7b) into the open reading frame of PB1 to test the feasibility of creating a cell-restricted H1N1pdm virus since let-7b is abundant in human bronchial epithelial cells. Results. miR-let-7b is rich in human bronchial epithelial cells (HBE). Incorporation of the miR-let-7b-MRE confers upon the recombinant H1N1pdm virus susceptibility to miR-let-7b targeting, suggesting that the H1N1pdm and influenza A viruses can be engineered to exert the desired replication restrictive effect and decrease infectivity in vital tissues and organs. Conclusions. This approach provides an additional layer of biosafety and thus has great potential for the application in the rational development of safer and more effective influenza viral vaccines. Xiaoyue Shen, Wenkui Sun, Yi Shi, Zheng Xing, and Xin Su Copyright © 2015 Xiaoyue Shen et al. All rights reserved. Presence of Fatty Liver and the Relationship between Alcohol Consumption and Markers of Inflammation Wed, 18 Feb 2015 13:09:10 +0000 http://www.hindawi.com/journals/mi/2015/278785/ Background and Aims. Local and systemic inflammation represent a major feature of atherosclerotic cardiovascular disease (CVD) and are also linked to nonalcoholic fatty liver disease (NAFLD). Studies indicate that NAFLD might be a risk factor for CVD whereas low-to-moderate alcohol consumption is associated with lower cardiovascular morbidity and mortality compared to abstainers and heavy drinkers. We hypothesize that FLD interacts with the effect of alcohol intake on markers of inflammation, and thus potentially on cardiovascular risk. Methods and Results. We evaluated alcohol consumption, markers of inflammation and sonographic criteria of FLD in 515 subjects, representing a subsample of a cross-sectional population based study (Echinococcus multilocularis and Internal Diseases in Leutkirch (EMIL) Study). Presence of FLD was markedly reduced in subjects drinking 0–20 g alcohol/d (19%), compared to nondrinkers (35%) and heavy drinkers (34–44.9%). Serum concentrations of inflammatory markers were substantially higher in subjects with FLD. However, presence of FLD showed no effect on the association between alcohol consumption and inflammatory biomarkers. Conclusions. Based on data from a population-based sample, there is no evidence for a link between FLD, alcohol consumption, and inflammatory cardiovascular risk markers. However, larger prospective studies are needed to confirm this. Martin Kächele, Stefan Wolff, Wolfgang Kratzer, Mark Haenle, Jörg Homann, Gerlinde Trischler, Wolfgang Koenig, and Armin Imhof Copyright © 2015 Martin Kächele et al. All rights reserved. Role of Genetic Alterations in the NLRP3 and CARD8 Genes in Health and Disease Wed, 18 Feb 2015 06:21:07 +0000 http://www.hindawi.com/journals/mi/2015/846782/ The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease. G. V. Paramel, A. Sirsjö, and K. Fransén Copyright © 2015 G. V. Paramel et al. All rights reserved. Interleukin-1 as a Common Denominator from Autoinflammatory to Autoimmune Disorders: Premises, Perils, and Perspectives Mon, 16 Feb 2015 11:10:39 +0000 http://www.hindawi.com/journals/mi/2015/194864/ A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behçet’s disease, gout, Sjögren’s syndrome, interstitial lung diseases, and Still’s disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems. Giuseppe Lopalco, Luca Cantarini, Antonio Vitale, Florenzo Iannone, Maria Grazia Anelli, Laura Andreozzi, Giovanni Lapadula, Mauro Galeazzi, and Donato Rigante Copyright © 2015 Giuseppe Lopalco et al. All rights reserved. A Lipid Mediator Hepoxilin A3 Is a Natural Inducer of Neutrophil Extracellular Traps in Human Neutrophils Mon, 16 Feb 2015 09:00:22 +0000 http://www.hindawi.com/journals/mi/2015/520871/ Pulmonary exacerbations in cystic fibrosis airways are accompanied by inflammation, neutrophilia, and mucous thickening. Cystic fibrosis sputum contains a large amount of uncleared DNA contributed by neutrophil extracellular trap (NET) formation from neutrophils. The exact mechanisms of the induction of NETosis in cystic fibrosis airways remain unclear, especially in uninfected lungs of patients with early cystic fibrosis lung disease. Here we show that Hepoxilin A3, a proinflammatory eicosanoid, and the synthetic analog of Hepoxilin B3, PBT-3, directly induce NETosis in human neutrophils. Furthermore, we show that Hepoxilin A3-mediated NETosis is NADPH-oxidase-dependent at lower doses of Hepoxilin A3, while it is NADPH-oxidase-independent at higher doses. Together, these results demonstrate that Hepoxilin A3 is a previously unrecognized inducer of NETosis in cystic fibrosis lungs and may represent a new therapeutic target for treating cystic fibrosis and other inflammatory lung diseases. David N. Douda, Hartmut Grasemann, Cecil Pace-Asciak, and Nades Palaniyar Copyright © 2015 David N. Douda et al. All rights reserved. ISU201 Enhances the Resolution of Airway Inflammation in a Mouse Model of an Acute Exacerbation of Asthma Thu, 12 Feb 2015 17:24:02 +0000 http://www.hindawi.com/journals/mi/2015/405629/ Glucocorticoids are commonly used for treating asthma and its exacerbations but have well-recognised adverse effects and are not always effective. Few alternative treatments exist. Using a murine model of an acute exacerbation of asthma, we assessed the ability of ISU201, a novel protein drug, to suppress the inflammatory response when administered after induction of an exacerbation. Sensitised mice were chronically challenged with a low mass concentration of aerosolised ovalbumin, and then received a single moderate-level challenge to simulate an allergen-induced exacerbation. ISU201 was administered to mice 2 and 8 hours later, while pulmonary inflammation and expression of mRNA for chemokines and proinflammatory cytokines were assessed after 4, 12, and 24 hours. Relative to vehicle-treated controls, ISU201 suppressed accumulation of pulmonary neutrophils and eosinophils, while accelerating the decline in CXCL1, TNF-α, and IL-6 in lavage fluid and lung tissue. ISU201 significantly reduced peak expression of mRNA for the chemokines Cxcl9 and Cxcl10, the adhesion molecules Icam1 and Vcam1, and the proinflammatory cytokines Il1b, Il12p40, and Csf1. The ability of ISU201 to promote resolution of inflammation suggests that it may have potential as an alternative to glucocorticoids in the management of asthma, including when administered after the onset of an acute exacerbation. Yuka Hiroshima, Linda Garthwaite, Kenneth Hsu, Hyouna Yoo, Sang-Ho Park, Carolyn L. Geczy, Rakesh K. Kumar, and Cristan Herbert Copyright © 2015 Yuka Hiroshima et al. All rights reserved. The Olive Oil-Based Lipid Clinoleic Blocks Leukocyte Recruitment and Improves Survival during Systemic Inflammation: A Comparative In Vivo Study of Different Parenteral Lipid Emulsions Thu, 12 Feb 2015 11:18:58 +0000 http://www.hindawi.com/journals/mi/2015/757059/ Although fish oil-based and olive oil-based lipid emulsions have been shown to exert anti-inflammatory functions, the immunomodulating properties of lipids are still controversial. Therefore, we investigated the anti-inflammatory effect of three different parenterally administered lipid emulsions in vivo: olive oil-based Clinoleic, fish oil-based Smoflipid, and soybean oil-based Lipofundin. We observed leukocyte recruitment in inflamed murine cremaster muscle using intravital microscopy and survival in a murine model of LPS-induced systemic inflammation and analyzed expression of leukocyte and endothelial adhesion molecules. Olive oil-based Clinoleic and fish oil-based Smoflipid profoundly inhibited leukocyte adhesion compared to Lipofundin during LPS-induced inflammation of the murine cremaster muscle. In the trauma model of cremaster muscle inflammation, Lipofundin was the only lipid emulsion that even augmented leukocyte adhesion. In contrast to Smoflipid and Lipofundin, Clinoleic effectively blocked leukocyte recruitment and increased survival during lethal endotoxemia. Flow chamber experiments and analysis of adhesion molecule expression suggest that both endothelial and leukocyte driven mechanisms might contribute to anti-inflammatory effects of Clinoleic. We conclude that the anti-inflammatory properties of Clinoleic are superior to those of Smoflipid and Lipofundin even during systemic inflammation. Thus, these results should stimulate further studies investigating parenteral lipids as an anti-inflammatory strategy in critically ill patients. Kirsten Buschmann, Johannes Poeschl, Natascha Braach, Hannes Hudalla, Navina Kuss, and David Frommhold Copyright © 2015 Kirsten Buschmann et al. All rights reserved. Reduced Serum Butyrylcholinesterase Activity Indicates Severe Systemic Inflammation in Critically Ill Patients Wed, 11 Feb 2015 09:54:16 +0000 http://www.hindawi.com/journals/mi/2015/274607/ Systemic inflammation is an immune response to a nonspecific insult of either infectious or noninfectious origin and remains a challenge in the intensive care units with high mortality rate. Cholinergic neurotransmission plays an important role in the regulation of the immune response during inflammation. We hypothesized that the activity of butyrylcholinesterase (BChE) might serve as a marker to identify and prognose systemic inflammation. By using a point-of-care-testing (POCT) approach we measured BChE activity in patients with severe systemic inflammation and healthy volunteers. We observed a decreased BChE activity in patients with systemic inflammation, as compared to that of healthy individuals. Furthermore, BChE activity showed an inverse correlation with the severity of the disease. Although hepatic function has previously been found essential for BChE production, we show here that the reduced BChE activity associated with systemic inflammation occurs independently of and is thus not caused by any deficit in liver function in these patients. A POCT approach, used to assess butyrylcholinesterase activity, might further improve the therapy of the critically ill patients by minimizing time delays between the clinical assessment and treatment of the inflammatory process. Hence, assessing butyrylcholinesterase activity might help in early detection of inflammation. Aleksandar R. Zivkovic, Karsten Schmidt, Annette Sigl, Sebastian O. Decker, Thorsten Brenner, and Stefan Hofer Copyright © 2015 Aleksandar R. Zivkovic et al. All rights reserved. The Prevalence of Autoantibodies in Complex Regional Pain Syndrome Type I Sun, 08 Feb 2015 14:36:48 +0000 http://www.hindawi.com/journals/mi/2015/718201/ Autoimmunity has been suggested as one of the pathophysiologic mechanisms that may underlie complex regional pain syndrome (CRPS). Screening for antinuclear antibodies (ANA) is one of the diagnostic tests, which is usually performed if a person is suspected to have a systemic autoimmune disease. Antineuronal antibodies are autoantibodies directed against antigens in the central and/or peripheral nervous system. The aim of this study was to compare the prevalence of these antibodies in CRPS patients with the normal values of those antibodies in the healthy population. Twenty seven (33%) of the 82 CRPS patients of whom serum was available showed a positive ANA test. This prevalence is significantly higher than in the general population. Six patients (7.3%) showed a positive result for typical antineuronal antibodies. This proportion, however, does not deviate from that in the general population. Our findings suggest that autoantibodies may be associated with the pathophysiology of CRPS, at least in a subset of patients. Further research is needed into defining this subset and into the role of autoantibodies in the pathogenesis of CRPS. Maaike Dirckx, Marco W. J. Schreurs, Marissa de Mos, Dirk L. Stronks, and Frank J. P. M. Huygen Copyright © 2015 Maaike Dirckx et al. All rights reserved. Lipid Peroxidation-Mediated Inflammation Promotes Cell Apoptosis through Activation of NF-κB Pathway in Rheumatoid Arthritis Synovial Cells Thu, 05 Feb 2015 10:29:31 +0000 http://www.hindawi.com/journals/mi/2015/460310/ Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of multiple joints. The central pathogenesis of RA is the proliferation of synovial fibroblasts in response to inflammatory cytokines. However, some of the targeted therapies for inflammation reactions do not display significant clinical improvement after initiation of therapy. Thus, the relationship between inflammatory responses and RA therapy is still incompletely understood. In the present study, we proposed to determine whether enhanced inflammations may lead to cell apoptosis in rheumatoid arthritis synoviocytes. Our results indicated that products of lipid peroxidations, 4-HNE, may induce synovial intrinsic inflammations by activating NF-κB pathways and it may lead to cell apoptosis. Pharmacological inhibition of NF-κB activation may reduce the 4-HNE mediated inflammation responses and subsequent cell apoptosis. Our results may help to clarify the role of inflammations on RA development and imply that blocking NF-κB activation may be partly beneficial for human RA therapy. These findings might provide a mechanism-based rationale for developing new strategy to RA clinical therapy. Geng Yin, Ying Wang, Xiao-min Cen, Min Yang, Yan Liang, and Qi-bing Xie Copyright © 2015 Geng Yin et al. All rights reserved. Effects on Serum Fractalkine by Diet and Omega-3 Fatty Acid Intervention: Relation to Clinical Outcome Thu, 05 Feb 2015 06:26:22 +0000 http://www.hindawi.com/journals/mi/2015/373070/ Introduction. Fractalkine is a chemokine associated with atherosclerosis. Increased serum levels have been reported in unstable coronary artery disease (CAD) and to predict mortality in heart failure. Mediterranean-like diet and omega-3 fatty acids (n3-PUFA) have documented cardioprotective and anti-inflammatory effects. We have investigated the effect of Mediterranean-like dietary counseling and n-3 PUFA on serum fractalkine in an elderly population and its ability to predict cardiovascular disease (CVD). Materials and Methods. 563 men (age 64–75 yrs) at high risk of CAD were randomized into a 2 × 2 factorial designed trial for 3-year dietary counseling and/or n-3 PUFA supplementation (2.4 g/d). Circulating levels of fractalkine were measured at baseline and at end of study. Clinical events were recorded after 3 years. Results. Fractalkine levels were significantly reduced in all groups from baseline to 3 years (, all), but without between-group differences in changes. Fractalkine levels at baseline were not predictive for CVD events () or total mortality. Lower fractalkine levels were observed in smokers (). Conclusions. Reduced levels of fractalkine from baseline to 3 years were observed, however, without any influence of Mediterranean-like diet or n-3 PUFA supplementation. Fractalkine levels at baseline were not predictive for later CVD events. Kristian Laake, Ingebjørg Seljeflot, Morten Wang Fagerland, Ida Unhammer Njerve, Harald Arnesen, and Svein Solheim Copyright © 2015 Kristian Laake et al. All rights reserved. Autophagy Upregulation and Apoptosis Downregulation in DAHP and Triptolide Treated Cerebral Ischemia Mon, 02 Feb 2015 07:40:08 +0000 http://www.hindawi.com/journals/mi/2015/120198/ It has previously been demonstrated that ischemic stroke activates autophagy pathways; however, the mechanism remains unclear. The aim of this study is to further investigate the role that autophagy plays in cerebral ischemia. 2, 4-diamino-6-hydroxy-pyrimidine (DAHP), for its nitric oxide synthase (NOS) inhibiting neuroprotective effect, and triptolide (TP), for its anti-inflammatory property, were selected to administer pre middle cerebral artery occlusion (MCAO). The drugs were administered 12 hours prior to MCAO. Both magnetic resonance imaging (MRI) and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that the drugs reduce the area of infarction. Immunoblotting analysis revealed increases in Beclin-1 and myeloid cell leukelia-1(Mcl-1) in treated rats. This could be a contributing factor to the reduction in autophagy induced damage. Immunochemistry and western blot showed that mTOR expression in treated rats was marginally different 24 h after injury, and this could also be significant in the mechanism. Furthermore, terminal deoxynucleotidyl transferase- (TdT-) mediated dUTP nick end labeling (TUNEL) staining proved that the drugs are effective in reducing apoptosis. The upregulation of Beclin-1 and Mcl-1 and downregulation of Bcl-2, caspase-3, and the Bcl-2/Beclin-1 ratio infer that the neuroprotective effect of DAHP and TP act via the mediation of autophagy and apoptosis pathways. Yang Yang, Keqiang Gao, Zhiying Hu, Weiyun Li, Henry Davies, Shucai Ling, John A. Rudd, and Marong Fang Copyright © 2015 Yang Yang et al. All rights reserved. Allicin Alleviates Inflammation of Trinitrobenzenesulfonic Acid-Induced Rats and Suppresses P38 and JNK Pathways in Caco-2 Cells Mon, 02 Feb 2015 06:26:31 +0000 http://www.hindawi.com/journals/mi/2015/434692/ Background. Allicin has anti-inflammatory, antioxidative and proapoptotic properties. Aims. To evaluate the effects and investigate the mechanism of allicin on trinitrobenzenesulfonic acid-induced colitis, specifically with mesalazine or sulfasalazine. Methods. 80 rats were divided equally into 8 groups: control; trinitrobenzenesulfonic acid; allicin prevention; allicin; mesalazine; sulfasalazine; allicin + sulfasalazine, and mesalazine + allicin. Systemic and colonic inflammation parameters were analysed. In addition, protein and culture medium of Caco-2 cells treated with various concentrations of IL-1β or allicin were collected for investigation of IL-8, NF-κB p65 P38, ERK, and JNK. One-way ANOVA and Kruskal-Wallis test were used for parametric and nonparametric tests, respectively. Results. Allicin reduced the body weight loss of trinitrobenzenesulfonic acid-induced rats, histological score, serum TNF-α and IL-1β levels, and colon IL-1β mRNA level and induced serum IL-4 level, particularly in combination with mesalazine. In addition, 1 ng/mL IL-1β stimulated the P38, ERK, and JNK pathways, whereas pretreatment with allicin depressed this phenomenon, except for the ERK pathway. Conclusions. The inflammation induced by trinitrobenzenesulfonic acid is mitigated significantly by allicin treatment, particularly combined with mesalazine. Allicin inhibits the P38 and JNK pathways and the expression of NF-κB which explained the potential anti-inflammatory mechanisms of allicin. Chen Li, Weijian Lun, Xinmei Zhao, Shan Lei, Yandong Guo, Jiayi Ma, and Fachao Zhi Copyright © 2015 Chen Li et al. All rights reserved. Inflammatory Cytokines: Potential Biomarkers of Immunologic Dysfunction in Autism Spectrum Disorders Sun, 01 Feb 2015 09:45:31 +0000 http://www.hindawi.com/journals/mi/2015/531518/ Autism is a disorder of neurobiological origin characterized by problems in communication and social skills and repetitive behavior. After more than six decades of research, the etiology of autism remains unknown, and no biomarkers have been proven to be characteristic of autism. A number of studies have shown that the cytokine levels in the blood, brain, and cerebrospinal fluid (CSF) of autistic subjects differ from that of healthy individuals; for example, a series of studies suggests that interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) are significantly elevated in different tissues in autistic subjects. However, the expression of some cytokines, such as IL-1, IL-2, transforming growth factor-β (TGF-β), and granulocyte-macrophage colony-stimulating factor (GM-CSF), is controversial, and different studies have found various results in different tissues. In this review, we focused on several types of proinflammatory and anti-inflammatory cytokines that might affect different cell signal pathways and play a role in the pathophysiological mechanism of autistic spectrum disorders. Ningan Xu, Xiaohong Li, and Yan Zhong Copyright © 2015 Ningan Xu et al. All rights reserved. Role of COX-2/mPGES-1/Prostaglandin E2 Cascade in Kidney Injury Sun, 01 Feb 2015 09:05:27 +0000 http://www.hindawi.com/journals/mi/2015/147894/ COX-2/mPGES-1/PGE2 cascade plays critical roles in modulating many physiological and pathological actions in different organs. In the kidney, this cascade is of high importance in regulating fluid metabolism, blood pressure, and renal hemodynamics. Under some disease conditions, this cascade displays various actions in response to the different pathological insults. In the present review, the roles of this cascade in the pathogenesis of kidney injuries including diabetic and nondiabetic kidney diseases and acute kidney injuries were introduced and discussed. The new insights from this review not only increase the understanding of the pathological role of the COX-2/mPGES-1/PGE2 pathway in kidney injuries, but also shed new light on the innovation of the strategies for the treatment of kidney diseases. Zhanjun Jia, Yue Zhang, Guixia Ding, Kristina Marie Heiney, Songming Huang, and Aihua Zhang Copyright © 2015 Zhanjun Jia et al. All rights reserved.