Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Macadamia Oil Supplementation Attenuates Inflammation and Adipocyte Hypertrophy in Obese Mice Mon, 22 Sep 2014 07:27:12 +0000 Excess of saturated fatty acids in the diet has been associated with obesity, leading to systemic disruption of insulin signaling, glucose intolerance, and inflammation. Macadamia oil administration has been shown to improve lipid profile in humans. We evaluated the effect of macadamia oil supplementation on insulin sensitivity, inflammation, lipid profile, and adipocyte size in high-fat diet (HF) induced obesity in mice. C57BL/6 male mice (8 weeks) were divided into four groups: (a) control diet (CD), (b) HF, (c) CD supplemented with macadamia oil by gavage at 2 g/Kg of body weight, three times per week, for 12 weeks (CD + MO), and (d) HF diet supplemented with macadamia oil (HF + MO). CD and HF mice were supplemented with water. HF mice showed hypercholesterolemia and decreased insulin sensitivity as also previously shown. HF induced inflammation in adipose tissue and peritoneal macrophages, as well as adipocyte hypertrophy. Macadamia oil supplementation attenuated hypertrophy of adipocytes and inflammation in the adipose tissue and macrophages. Edson A. Lima, Loreana S. Silveira, Laureane N. Masi, Amanda R. Crisma, Mariana R. Davanso, Gabriel I. G. Souza, Aline B. Santamarina, Renata G. Moreira, Amanda Roque Martins, Luis Gustavo O. de Sousa, Sandro M. Hirabara, and Jose C. Rosa Neto Copyright © 2014 Edson A. Lima et al. All rights reserved. Role of Cytokines and Toll-Like Receptors in the Immunopathogenesis of Guillain-Barré Syndrome Mon, 22 Sep 2014 06:27:11 +0000 Guillain-Barré syndrome (GBS) is an autoimmune disease of the peripheral nervous system, mostly triggered by an aberrant immune response to an infectious pathogen. Although several infections have been implicated in the pathogenesis of GBS, not all such infected individuals develop this disease. Moreover, infection with a single agent might also lead to different subtypes of GBS emphasizing the role of host factors in the development of GBS. The host factors regulate a broad range of inflammatory processes that are involved in the pathogenesis of autoimmune diseases including GBS. Evidences suggest that systemically and locally released cytokines and their involvement in immune-mediated demyelination and axonal damage of peripheral nerves are important in the pathogenesis of GBS. Toll-like receptors (TLRs) link innate and adaptive immunity through transcription of several proinflammatory cytokines. TLR genes may increase susceptibility to microbial infections; an attenuated immune response towards antigen and downregulation of cytokines occurs due to mutation in the gene. Herein, we discuss the crucial role of host factors such as cytokines and TLRs that activate the immune response and are involved in the pathogenesis of the disease. Kishan Kumar Nyati and Kashi Nath Prasad Copyright © 2014 Kishan Kumar Nyati and Kashi Nath Prasad. All rights reserved. Immunometabolism: Molecular Mechanisms, Diseases, and Therapies Mon, 22 Sep 2014 06:07:17 +0000 José Cesar Rosa Neto, Fábio Santos Lira, and William Tadeu Festuccia Copyright © 2014 José Cesar Rosa Neto et al. All rights reserved. Troglitazone and Δ2Troglitazone Enhance Adiponectin Expression in Monocytes/Macrophages through the AMP-Activated Protein Kinase Pathway Mon, 22 Sep 2014 05:36:25 +0000 Accumulating evidence indicates that the regimen to increase adiponectin will provide a novel therapeutic strategy for inflammation and cardiovascular disorders. Here, we tested the effect of troglitazone (TG) and its newly synthesized derivative, 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-2,4-thiazolidinedione (Δ2troglitazone, (Δ2TG)), on the adiponectin expression in monocytes/macrophages and the relative mechanisms. The expression of adiponectin was located in macrophages of atherosclerotic lesions from patients and cholesterol-fed rabbits. TG and Δ2TG enhanced adiponectin mRNA and protein expression in THP-1 cells by quantitative real-time PCR, Western blot, and immunocytochemistry. TG induced adiponectin mRNA expression through a PPARγ-dependent pathway whereas Δ2TG enhanced adiponectin mRNA expression through a PPARγ-independent pathway in THP-1 cells. Both TG and Δ2TG enhanced adiponectin mRNA expression through AMP-activated protein kinase (AMPK) activation. TG and Δ2TG decreased the adhesion of THP-1 cells to TNF-α-treated HUVECs and the inhibitory effect was abolished by specific antiadiponectin antibodies. TG- and Δ2TG-induced suppression on monocyte adhesion were inhibited by a selective AMPK inhibitor compound C. Our data suggest that the inhibitory effect of TG and Δ2TG on monocyte adhesion might be at least in part through de novo adiponectin expression and activation of an AMPK-dependent pathway, which might play an important role in anti-inflammation and antiatherosclerosis. Jaw-Shiun Tsai, Lee-Ming Chuang, Ching-Shih Chen, Chan-Jung Liang, Yuh-Lien Chen, and Ching-Yu Chen Copyright © 2014 Jaw-Shiun Tsai et al. All rights reserved. An In Vitro Model to Evaluate the Impact of the Soluble Factors from the Colonic Mucosa of Collagenous Colitis Patients on T Cells: Enhanced Production of IL-17A and IL-10 from Peripheral CD4+ T Cells Sun, 21 Sep 2014 07:37:15 +0000 Soluble factors from intestinal mucosal cells contribute to immune homeostasis in the gut. We have established an in vitro model to investigate the regulatory role of soluble factors from inflamed intestinal mucosa of collagenous colitis (CC) patients in the differentiation of T cells. Peripheral blood CD4+ T cells from healthy donors were polyclonally activated in the presence of conditioned medium (CM) generated from denuded biopsies (DNB) or isolated lamina propria mononuclear cells (LPMCs) from mucosal biopsies from CC patients compared to noninflamed controls, to determine proliferation and secretion of cytokines involved in T-cell differentiation. Compared to controls, we observed significantly increased production of the proinflammatory cytokines IFN-γ, IL-17A, IL-6, and IL-1β and the anti-inflammatory cytokines IL-4 and IL-10 in the presence of CC-DNB-CM. The most pronounced effect of CC-LPMC-CM on peripheral CD4+ T cells was a trend towards increased production of IL-17A and IL-10. A trend towards reduced inhibition of T-cell proliferation was noted in the presence of CC-DNB-CM. In conclusion, our in vitro model reveals implications of soluble factors from CC colonic mucosa on peripheral T cells, enhancing their production of both pro- and anti-inflammatory cytokines. Ashok Kumar Kumawat, Nils Nyhlin, Anna Wickbom, Curt Tysk, Johan Bohr, Olof Hultgren, and Elisabeth Hultgren Hörnquist Copyright © 2014 Ashok Kumar Kumawat et al. All rights reserved. Biomarker Analysis Revealed Distinct Profiles of Innate and Adaptive Immunity in Infants with Ocular Lesions of Congenital Toxoplasmosis Thu, 18 Sep 2014 11:17:41 +0000 Toxoplasma gondii is the main infectious cause of human posterior retinochoroiditis, the most frequent clinical manifestation of congenital toxoplasmosis. This investigation was performed after neonatal screening to identify biomarkers of immunity associated with immunopathological features of the disease by flow cytometry. The study included infected infants without NRL and with retinochoroidal lesions (ARL, ACRL, and CRL) as well as noninfected individuals (NI). Our data demonstrated that leukocytosis, with increased monocytes and lymphocytes, was a relevant hematological biomarker of ARL. Immunophenotypic analysis also revealed expansion of CD14+CD16+HLA- monocytes and cytotoxic NK-cells in ARL. Moreover, augmented TCRγδ+ and CD8+ T-cell counts were apparently good biomarkers of morbidity. Biomarker network analysis revealed that complex and intricated networks underscored the negative correlation of monocytes with NK- and B-cells in NRL. The remarkable lack of connections involving B-cells and a relevant shift of NK-cell connections from B-cells toward T-cells observed in ARL were outstanding. A tightly connected biomarker network was observed in CRL, with relevant connections of NK- and CD8+ T-cells with a broad range of cell subsets. Our findings add novel elements to the current knowledge on the innate and adaptive immune responses in congenital toxoplasmosis. Anderson Silva Machado, Ana Carolina Aguiar Vasconcelos Carneiro, Samantha Ribeiro Béla, Gláucia Manzan Queiroz Andrade, Daniel Vitor Vasconcelos-Santos, José Nélio Januário, Jordana G. Coelho-dos-Reis, Eloisa Amália Vieira Ferro, Andréa Teixeira-Carvalho, Ricardo Wagner Almeida Vitor, Olindo Assis Martins-Filho, and UFMG Congenital Toxoplasmosis Brazilian Group —UFMG-CTBG Copyright © 2014 Anderson Silva Machado et al. All rights reserved. No Signs of Inflammation during Knee Surgery with Ischemia: A Study Involving Inhaled Nitric Oxide Thu, 18 Sep 2014 08:40:04 +0000 Nitric oxide donors and inhaled nitric oxide (iNO) may decrease ischemia/reperfusion injury as reported in animal and human models. We investigated whether the attenuation of reperfusion injury, seen by others, in patients undergoing knee arthroplasty could be reproduced when patients had spinal anesthesia. 45 consecutive patients were randomized into three groups (). Groups 1 and 3 were receiving iNO 80 ppm or placebo (nitrogen, N2) throughout the entire operation, and group 2 only received iNO in the beginning and at the end of the operation. Blood samples were collected before surgery, at the end of the surgery, and 2 hours postoperatively. Muscle biopsies were taken from quadriceps femoris muscle before and after ischemia. There were no increases in plasma levels of soluble adhesion molecules: ICAM, VCAM, P-selectin, E-selectin, or of HMGB1, in any of the groups. There were low numbers of CD68+ macrophages and of endothelial cells expression of ICAM, VCAM, and P-selectin in the muscle analyzed by immunohistochemistry, prior to and after ischemia. No signs of endothelial cell activation or inflammatory response neither systemically nor locally could be detected. The absence of inflammatory response questions this model of ischemia/reperfusion, but may also be related to the choice of anesthetic method EudraCTnr. Lars Hållström, Claes Frostell, Anders Herrlin, Eva Lindroos, Ingrid Lundberg, and Anne Soop Copyright © 2014 Lars Hållström et al. All rights reserved. Toll-Like Receptor 2 as a Regulator of Oral Tolerance in the Gastrointestinal Tract Wed, 17 Sep 2014 11:35:28 +0000 Food allergy, other adverse immune responses to foods, inflammatory bowel disease, and eosinophilic esophagitis have become increasingly common in the last 30 years. It has been proposed in the “hygiene hypothesis” that dysregulated immune responses to environmental microbial stimuli may modify the balance between tolerance and sensitization in some patients. Of the pattern recognition receptors that respond to microbial signals, toll-like receptors (TLRs) represent the most investigated group. The relationship between allergy and TLR activation is currently at the frontier of immunology research. Although TLR2 is abundant in the mucosal environment, little is known about the complex relationship between bystander TLR2 activation by the commensal microflora and the processing of oral antigens. This review focuses on recent advances in our understanding of the relationship between TLR2 and oral tolerance, with an emphasis on regulatory T cells, eosinophils, B cells, IgA, intestinal regulation, and commensal microbes. Matthew C. Tunis and Jean S. Marshall Copyright © 2014 Matthew C. Tunis and Jean S. Marshall. All rights reserved. Preventive Effects of Chitosan Coacervate Whey Protein on Body Composition and Immunometabolic Aspect in Obese Mice Wed, 17 Sep 2014 09:33:02 +0000 Functional foods containing bioactive compounds of whey may play an important role in prevention and treatment of obesity. The aim of this study was to investigate the prospects of the biotechnological process of coacervation of whey proteins (CWP) in chitosan and test its antiobesogenic potential. Methods. CWP (100 mg·kg·day) was administered in mice with diet-induced obesity for 8 weeks. The animals were divided into four groups: control normocaloric diet gavage with water (C) or coacervate (C-CWP), and high fat diet gavage with water (HF) or coacervate (HF-CWP). Results. HF-CWP reduced weight gain and serum lipid fractions and displayed reduced adiposity and insulin. Adiponectin was significantly higher in HF-CWP group when compared to the HF. The level of LPS in HF-W group was significantly higher when compared to HF-CWP. The IL-10 showed an inverse correlation between the levels of insulin and glucose in the mesenteric adipose tissue in the HF-CWP group. CWP promoted an increase in both phosphorylation AMPK and the amount of ATGL in the mesenteric adipose tissue in HF-CWP group. Conclusion. CWP was able to modulate effects, possibly due to its high biological value of proteins. We observed a protective effect against obesity and improved the inflammatory milieu of white adipose tissue. Gabriel Inácio de Morais Honorato de Souza, Aline Boveto Santamarina, Aline Alves de Santana, Fábio Santos Lira, Rachel de Laquila, Mayara Franzoi Moreno, Eliane Beraldi Ribeiro, Claudia Maria da Penha Oller do Nascimento, Bruno Rodrigues, Elisa Esposito, and Lila Missae Oyama Copyright © 2014 Gabriel Inácio de Morais Honorato de Souza et al. All rights reserved. Markers of Inflammation and Fibrosis in the Orbital Fat/Connective Tissue of Patients with Graves’ Orbitopathy: Clinical Implications Wed, 17 Sep 2014 00:00:00 +0000 Purpose. To assess FGF-, TGF-, and COX2 expression and immunocompetent cells in the orbital tissue of patients with severe and mild Graves’ orbitopathy. Patients and Methods. Orbital tissue was taken from 27 patients with GO: (1) severe GO (), the mean clinical activity score (CAS) being 8.5 (SD 2.5); and (2) mild GO (), the mean CAS being 2.2 (SD 0.8), and from 10 individuals undergoing blepharoplasty. The expression of CD4+, CD8+, CD20+, and CD68 and FGF-, TGF-, and COX2 in the orbital tissue was evaluated by immunohistochemical methods. Results. We demonstrated predominant CD4+ T cells in severe GO. CD68 expression was observed in the fibrous connective area of mild GO and was robust in severe GO, while the prominent TGF- expression was seen in all GO. Increased FGF- expression was observed in the fibroblasts and adipocytes of severe GO. No expression of COX2 was found in patients with GO. Conclusions. Macrophages and CD4 T lymphocytes are both engaged in the active/severe and long stage of inflammation in the orbital tissue. FGF- and TGF- expression may contribute to tissue remodeling, fibrosis, and perpetuation of inflammation in the orbital tissue of GO especially in severe GO. Przemyslaw Pawlowski, Joanna Reszec, Anja Eckstein, Kristian Johnson, Andrzej Grzybowski, Lech Chyczewski, and Janusz Mysliwiec Copyright © 2014 Przemyslaw Pawlowski et al. All rights reserved. Intestinal Parasites Coinfection Does Not Alter Plasma Cytokines Profile Elicited in Acute Malaria in Subjects from Endemic Area of Brazil Tue, 16 Sep 2014 12:06:07 +0000 In Brazil, malaria is prevalent in the Amazon region and these regions coincide with high prevalence of intestinal parasites but few studies explore the interaction between malaria and other parasites. Therefore, the present study evaluates changes in cytokine, chemokine, C-reactive protein, and nitric oxide (NO) concentrations in 264 individuals, comparing plasma from infected individuals with concurrent malaria and intestinal parasites to individuals with either malaria infection alone and uninfected. In the studied population 24% of the individuals were infected with Plasmodium and 18% coinfected with intestinal parasites. Protozoan parasites comprised the bulk of the intestinal parasites infections and subjects infected with intestinal parasites were more likely to have malaria. The use of principal component analysis and cluster analysis associated increased levels of IL-6, TNF-α, IL-10, and CRP and low levels of IL-17A predominantly with individuals with malaria alone and coinfected individuals. In contrast, low levels of almost all inflammatory mediators were associated predominantly with individuals uninfected while increased levels of IL-17A were associated predominantly with individuals with intestinal parasites only. In conclusion, our data suggest that, in our population, the infection with intestinal parasites (mainly protozoan) does not modify the pattern of cytokine production in individuals infected with P. falciparum and P. vivax. Juan Camilo Sánchez-Arcila, Daiana de Souza Perce-da-Silva, Mariana Pinheiro Alves Vasconcelos, Rodrigo Nunes Rodrigues-da-Silva, Virginia Araujo Pereira, Cesarino Junior Lima Aprígio, Cleoni Alves Mendes Lima, Bruna de Paula Fonseca e Fonseca, Dalma Maria Banic, Josué da Costa Lima-Junior, and Joseli Oliveira-Ferreira Copyright © 2014 Juan Camilo Sánchez-Arcila et al. All rights reserved. The Antioxidant Profiles, Lysosomal and Membrane Enzymes Activity in Patients with Acute Pancreatitis Mon, 15 Sep 2014 00:00:00 +0000 Oxidative stress and inflammatory mediators, such as IL-6, play an important role in the pathophysiology of acute pancreatitis. The study was aimed to assess the degree of the pro/antioxidative imbalance and estimate which antioxidant plays a role in the maintenance of pro/antioxidative balance during acute pancreatitis. The study was investigated in the blood of 32 patients with acute pancreatitis and 37 healthy subjects. IL-6 concentration as early marker of inflammation was determinated. The intensity of oxidative stress was assessed by TBARS concentration. To investigate antioxidative status, the GPx and Cu/Zn SOD activities and the levels of GSH, MT, SH groups, and TRAP were measured. The concentrations of Cu and Zn as ions participating in the maintenance of antioxidant enzymes stability and playing a role in the course of disease were determinated. The activities of GGT, AAP, NAG, and β-GD as markers of tissue damage were also measured. An increase in IL-6 concentration, which correlated with Ranson criteria, and an increase in GPx activity, levels of MT, TBARS, or GGT, and NAG activities in patients group compared to healthy subjects were demonstrated. A decrease in GSH level in patients group compared to control group was noted. The studies suggest that GPx/GSH and MT play the role of the first line of defence against oxidative stress and pro/antioxidant imbalance in the course of acute pancreatitis. Halina Milnerowicz, Radosław Bukowski, Monika Jabłonowska, Milena Ściskalska, and Stanisław Milnerowicz Copyright © 2014 Halina Milnerowicz et al. All rights reserved. MicroRNA-146a Decreases High Glucose/Thrombin-Induced Endothelial Inflammation by Inhibiting NAPDH Oxidase 4 Expression Sun, 14 Sep 2014 06:22:55 +0000 Diabetes is associated with hyperglycemia and increased thrombin production. However, it is unknown whether a combination of high glucose and thrombin can modulate the expression of NAPDH oxidase (Nox) subtypes in human aortic endothelial cells (HAECs). Moreover, we investigated the role of a diabetes-associated microRNA (miR-146a) in a diabetic atherothrombosis model. We showed that high glucose (HG) exerted a synergistic effect with thrombin to induce a 10.69-fold increase in Nox4 mRNA level in HAECs. Increased Nox4 mRNA expression was associated with increased Nox4 protein expression and ROS production. Inflammatory cytokine kit identified that the treatment increased IL-8 and IL-6 levels. Moreover, HG/thrombin treatment caused an 11.43-fold increase of THP-1 adhesion to HAECs. In silico analysis identified the homology between miR-146a and the 3′-untranslated region of the Nox4 mRNA, and a luciferase reporter assay confirmed that the miR-146a mimic bound to this Nox4 regulatory region. Additionally, miR-146a expression was decreased to 58% of that in the control, indicating impaired feedback restraint of HG/thrombin-induced endothelial inflammation. In contrast, miR-146a mimic transfection attenuated HG/thrombin-induced upregulation of Nox4 expression, ROS generation, and inflammatory phenotypes. In conclusion, miR-146a is involved in the regulation of endothelial inflammation via modulation of Nox4 expression in a diabetic atherothrombosis model. Huang-Joe Wang, Yuan-Li Huang, Ya-Yun Shih, Hsing-Yu Wu, Ching-Tien Peng, and Wan-Yu Lo Copyright © 2014 Huang-Joe Wang et al. All rights reserved. Interplay of Inflammation, Immunity, and Organ-Specific Adiposity with Cardiovascular Risk Sun, 14 Sep 2014 06:02:47 +0000 Massimiliano M. Corsi Romanelli, Gianluca Iacobellis, and Massimo Locati Copyright © 2014 Massimiliano M. Corsi Romanelli et al. All rights reserved. Cytokines and Disease Sun, 14 Sep 2014 05:22:17 +0000 Arkadiusz Orzechowski, Agueda A. Rostagno, Sabina Pucci, and Gilles Chiocchia Copyright © 2014 Arkadiusz Orzechowski et al. All rights reserved. Changes in Cerebrospinal Fluid Biomarkers in Human Herpesvirus-6-Associated Acute Encephalopathy/Febrile Seizures Thu, 11 Sep 2014 09:34:29 +0000 To determine the involvement of oxidative stress in the pathogenesis of acute encephalopathy associated with human herpesvirus-6 (HHV-6) infection, we measured the levels of oxidative stress markers 8-hydroxy-2′-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct (HEL), tau protein, and cytokines in cerebrospinal fluid (CSF) obtained from patients with HHV-6-associated acute encephalopathy (HHV-6 encephalopathy) and complex febrile seizures associated with HHV-6 (HHV-6 complex FS) . We also examined changes in CSF-8OHdG and CSF-HEL levels in patients with HHV-6 encephalopathy before and after treatment with edaravone, a free radical scavenger. CSF-8-OHdG levels in HHV-6 encephalopathy and HHV-6 complex FS were significantly higher than in control subjects. In contrast, CSF-HEL levels showed no significant difference between groups. The levels of total tau protein in HHV-6 encephalopathy were significantly higher than in control subjects. In six patients with HHV-6 infection (5 encephalopathy and 1 febrile seizure), the CSF-8-OHdG levels of five patients decreased after edaravone treatment. Our results suggest that oxidative DNA damage is involved in acute encephalopathy associated with HHV-6 infection. Naoyuki Tanuma, Rie Miyata, Keisuke Nakajima, Akihisa Okumura, Masaya Kubota, Shin-ichiro Hamano, and Masaharu Hayashi Copyright © 2014 Naoyuki Tanuma et al. All rights reserved. The Influence of Autologous Bone Marrow Stem Cell Transplantation on Matrix Metalloproteinases in Patients Treated for Acute ST-Elevation Myocardial Infarction Thu, 11 Sep 2014 09:02:45 +0000 Background. Matrix metalloproteinase-9 (MMP-9), regulated by tissue inhibitor of metalloproteinase-9 (TIMP-1) and the extracellular matrix metalloproteinase inducer (EMMPRIN), contributes to plaque instability. Autologous stem cells from bone marrow (mBMC) treatment are suggested to reduce myocardial damage; however, limited data exists on the influence of mBMC on MMPs. Aim. We investigated the influence of mBMC on circulating levels of MMP-9, TIMP-1, and EMMPRIN at different time points in patients included in the randomized Autologous Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial (). Gene expression analyses were additionally performed. Results. After 2-3 weeks we observed a more pronounced increase in MMP-9 levels in the mBMC group, compared to controls (), whereas EMMPRIN levels were reduced from baseline to 2-3 weeks and 3 months in both groups (). Gene expression of both MMP-9 and EMMPRIN was reduced from baseline to 3 months. MMP-9 and EMMPRIN were significantly correlated to myocardial injury (CK: and , resp.) and infarct size (SPECT: and , resp.). Conclusion. The results indicate that the regulation of metalloproteinases is important during AMI, however, limited influenced by mBMC. Eline Bredal Furenes, Trine Baur Opstad, Svein Solheim, Ketil Lunde, Harald Arnesen, and Ingebjørg Seljeflot Copyright © 2014 Eline Bredal Furenes et al. All rights reserved. Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B2 and B1 Receptors Wed, 10 Sep 2014 06:57:05 +0000 Inhibitors of serine peptidases (ISPs) expressed by Leishmania major enhance intracellular parasitism in macrophages by targeting neutrophil elastase (NE), a serine protease that couples phagocytosis to the prooxidative TLR4/PKR pathway. Here we investigated the functional interplay between ISP-expressing L. major and the kallikrein-kinin system (KKS). Enzymatic assays showed that NE inhibitor or recombinant ISP-2 inhibited KKS activation in human plasma activated by dextran sulfate. Intravital microscopy in the hamster cheek pouch showed that topically applied L. major promastigotes (WT and mutants) potently induced plasma leakage through the activation of bradykinin B2 receptors (B2R). Next, using mAbs against kininogen domains, we showed that these BK-precursor proteins are sequestered by L. major promastigotes, being expressed at higher % in the mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake of L. major revealed that antagonists of B2R or B1R reversed the upregulated uptake of mutants without inhibiting macrophage internalization of WT L. major. Collectively, our results suggest that L. major ISP-2 fine-tunes macrophage phagocytosis by inhibiting the pericellular release of proinflammatory kinins from surface bound kininogens. Ongoing studies should clarify whether L. major ISP-2 subverts TLR4/PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B2R/B1R. Erik Svensjö, Larissa Nogueira de Almeida, Lucas Vellasco, Luiz Juliano, and Julio Scharfstein Copyright © 2014 Erik Svensjö et al. All rights reserved. Insulin-Like Growth Factor-I Induces Arginase Activity in Leishmania amazonensis Amastigote-Infected Macrophages through a Cytokine-Independent Mechanism Tue, 09 Sep 2014 12:16:23 +0000 Leishmania (Leishmania) amazonensis exhibits peculiarities in its interactions with hosts. Because amastigotes are the primary form associated with the progression of infection, we studied the effect of insulin-like growth factor (IGF)-I on interactions between L. (L.) amazonensis amastigotes and macrophages. Upon stimulation of infected macrophages with IGF-I, we observed decreased nitric oxide production but increased arginase expression and activity, which lead to increased parasitism. However, stimulation of amastigote-infected macrophages with IGF-I did not result in altered cytokine levels compared to unstimulated controls. Because IGF-I is present in tissue fluids and also within macrophages, we examined the possible effect of this factor on phosphatidylserine (PS) exposure on amastigotes, seen previously in tissue-derived amastigotes leading to increased parasitism. Stimulation with IGF-I induced PS exposure on amastigotes but not on promastigotes. Using a PS-liposome instead of amastigotes, we observed that the PS-liposome but not the control phosphatidylcholine-liposome led to increased arginase activity in macrophages, and this process was not blocked by anti-TGF-β antibodies. Our results suggest that in L. (L.) amazonensis amastigote-infected macrophages, IGF-I induces arginase activity directly in amastigotes and in macrophages through the induction of PS exposure on amastigotes in the latter, which could lead to the alternative activation of macrophages through cytokine-independent mechanisms. Celia Maria Vieira Vendrame, Marcia Dias Teixeira Carvalho, Andre Gustavo Tempone, and Hiro Goto Copyright © 2014 Celia Maria Vieira Vendrame et al. All rights reserved. Resolution of Sterile Inflammation: Role for Vitamin C Tue, 09 Sep 2014 06:59:31 +0000 Introduction. Macrophage reprogramming is vital for resolution of acute inflammation. Parenteral vitamin C (VitC) attenuates proinflammatory states in murine and human sepsis. However information about the mechanism by which VitC regulates resolution of inflammation is limited. Methods. To examine whether physiological levels of VitC modulate resolution of inflammation, we used transgenic mice lacking L-gulono-γ-lactone oxidase. VitC sufficient/deficient mice were subjected to a thioglycollate-elicited peritonitis model of sterile inflammation. Some VitC deficient mice received daily parenteral VitC (200 mg/kg) for 3 or 5 days following thioglycollate infusion. Peritoneal macrophages harvested on day 3 or day 5 were examined for intracellular VitC levels, pro- and anti-inflammatory protein and lipid mediators, mitochondrial function, and response to lipopolysaccharide (LPS). The THP-1 cell line was used to determine the modulatory activities of VitC in activated human macrophages. Results. VitC deficiency significantly delayed resolution of inflammation and generated an exaggerated proinflammatory response to in vitro LPS stimulation. VitC sufficiency and in vivo VitC supplementation restored macrophage phenotype and function in VitC deficient mice. VitC loading of THP-1 macrophages attenuated LPS-induced proinflammatory responses. Conclusion. VitC sufficiency favorably modulates macrophage function. In vivo or in vitro VitC supplementation restores macrophage phenotype and function leading to timely resolution of inflammation. Bassem M. Mohammed, Bernard J. Fisher, Quoc K. Huynh, Dayanjan S. Wijesinghe, Charles E. Chalfant, Donald F. Brophy, Alpha A. Fowler III, and Ramesh Natarajan Copyright © 2014 Bassem M. Mohammed et al. All rights reserved. TLR4-Mediated Blunting of Inflammatory Responses to Eccentric Exercise in Young Women Tue, 09 Sep 2014 06:14:19 +0000 This study assessed the inflammatory response mediated by the toll-like receptor 4 (TLR4) signaling pathway after acute eccentric exercise before and after an eccentric training program in women. Twenty women performed two acute eccentric bouts using a squat machine over a ~9 week interval. The training group (TG) carried out an eccentric training program during 6 weeks, while the control group (CG) did not follow any training. Protein content of markers involved in the TLR4-mediated activation of several nuclear transcription factors, such as nuclear factor κB (NF-κB), and interferon regulatory transcription factor 3 (IRF3), was analyzed. The inflammatory response after the first acute bout was similar between TG and CG, showing an upregulation of all the markers analyzed, with the exception of IRF3. After the second bout, the upregulation of TLR4 signaling pathway was blunted in TG, but not in CG, through both the myeloid differentiation factor 88- and toll/interleukin-1 receptor domain containing adapter inducing interferon-β-dependent pathways. These results highlight the role of the TLR4 in controlling the exercise-induced inflammatory response in young women. More importantly, these data suggest eccentric training may help to prevent TLR4 activation principally through NF-κB, and perhaps IRF3, downstream signaling in this population. Rodrigo Fernandez-Gonzalo, José A. De Paz, Paula Rodriguez-Miguelez, María J. Cuevas, and Javier González-Gallego Copyright © 2014 Rodrigo Fernandez-Gonzalo et al. All rights reserved. Regulation of Hemichannels and Gap Junction Channels by Cytokines in Antigen-Presenting Cells Tue, 09 Sep 2014 06:03:40 +0000 Autocrine and paracrine signals coordinate responses of several cell types of the immune system that provide efficient protection against different challenges. Antigen-presenting cells (APCs) coordinate activation of this system via homocellular and heterocellular interactions. Cytokines constitute chemical intercellular signals among immune cells and might promote pro- or anti-inflammatory effects. During the last two decades, two membrane pathways for intercellular communication have been demonstrated in cells of the immune system. They are called hemichannels (HCs) and gap junction channels (GJCs) and provide new insights into the mechanisms of the orchestrated response of immune cells. GJCs and HCs are permeable to ions and small molecules, including signaling molecules. The direct intercellular transfer between contacting cells can be mediated by GJCs, whereas the release to or uptake from the extracellular milieu can be mediated by HCs. GJCs and HCs can be constituted by two protein families: connexins (Cxs) or pannexins (Panxs), which are present in almost all APCs, being Cx43 and Panx1 the most ubiquitous members of each protein family. In this review, we focus on the effects of different cytokines on the intercellular communication mediated by HCs and GJCs in APCs and their impact on purinergic signaling. Pablo J. Sáez, Kenji F. Shoji, Adam Aguirre, and Juan C. Sáez Copyright © 2014 Pablo J. Sáez et al. All rights reserved. MSH Blunts Endotoxin-Induced MuRF1 and Atrogin-1 Upregulation in Skeletal Muscle by Modulating NF-B and Akt/FoxO1 Pathway Tue, 09 Sep 2014 05:58:22 +0000 Alpha melanocyte stimulating hormone (MSH) has been shown to have anti-inflammatory and anticachectic actions. We hypothesized that MSH administration could attenuate the effect of lipopolysaccharide (LPS) on the skeletal muscle through modifications in IGF-Akt-FoxO1 pathway, or/and in serum corticosterone. Adult male Wistar rats were injected with LPS and/or MSH. MSH administration reduced LPS-induced increase in liver TNF and serum nitrites as well as NF-B activation in skeletal muscle. In contrast, αMSH was not able to prevent the stimulatory effect of LPS on serum concentration of ACTH and corticosterone. LPS decreased serum levels of IGF-I and IGFBP3 and their expression in the liver (). However IGFBP3 expression in the gastrocnemius was increased by LPS. Treatment with αMSH prevented the effects of LPS on IGFBP3 but not on IGF-I. In the gastrocnemius αMSH blocked LPS-induced decrease in pAkt as well as the increase in pNF-B(p65), FoxO1, atrogin-1, and MuRF1 levels. These results suggest that MSH blunts skeletal muscle response to endotoxin by downregulating atrogenes and FoxO1 at least in part by controlling NF-B activation and Akt signalling, but not through modifications in the secretion of corticosterone or IGF-I. Ana Isabel Martín, Ana Belén Gómez-SanMiguel, Carolina Gómez-Moreira, María Ángeles Villanúa, and Asunción López-Calderón Copyright © 2014 Ana Isabel Martín et al. All rights reserved. Oxidative Damage and Antioxidative Therapy in Systemic Sclerosis Mon, 08 Sep 2014 06:41:08 +0000 Systemic sclerosis (SSc) is an autoimmune connective tissue disorder of unknown etiology. This disease is characterized by a large variety of clinical patterns, which include the fibrosis of skin and visceral organs causing a variety of clinical manifestations. Genetic and environmental factors participate in the etiology of this disease; however, recently many studies underline the oxidative background influencing the course and complications of this disease. Reactive oxygen species (ROS) synthesized in SSc can mediate extra- and intracellular oxidative processes affecting endothelial cells and fibroblasts. The estimation of prooxidative markers in the pathogenesis of SSc can enable the identification of useful markers for disease activity and, thus, may help in planning appropriate therapy focusing on the fibrotic or vascular pattern. Recently, many attempts have been made to find antioxidative molecules (nutritional and pharmacological) reducing the prooxidant state in a variety of cells—mainly in endothelium and proliferating fibroblasts. This paper presents both the background of oxidative stress processes in systemic sclerosis mediated by different mechanisms and the evidence suggesting which of the dietary and pharmacological antioxidants can be used as therapeutic targets for this disease. Bogna Grygiel-Górniak and Mariusz Puszczewicz Copyright © 2014 Bogna Grygiel-Górniak and Mariusz Puszczewicz. All rights reserved. Epigallocatechin Gallate Attenuates Proliferation and Oxidative Stress in Human Vascular Smooth Muscle Cells Induced by Interleukin-1 via Heme Oxygenase-1 Sun, 07 Sep 2014 11:49:25 +0000 Proliferation of vascular smooth muscle cells (VSMCs) triggered by inflammatory stimuli and oxidative stress contributes importantly to atherogenesis. The association of green tea consumption with cardiovascular protection has been well documented in epidemiological observations, however, the underlying mechanisms remain unclear. This study aimed to elucidate the effects of the most active green tea catechin derivative, (−)-epigallocatechin-3-gallate (EGCG), in human aortic smooth muscle cells (HASMCs), focusing particularly on the role of a potent anti-inflammatory and antioxidative enzyme heme oxygenase-1 (HO-1). We found that pretreatment of EGCG dose- and time-dependently induced HO-1 protein levels in HASMCs. EGCG inhibited interleukin- (IL-)1-induced HASMC proliferation and oxidative stress in a dose-dependent manner. The HO-1 inducer CoPPIX decreased IL-1-induced cell proliferation, whereas the HO-1 enzyme inhibitor ZnPPIX significantly reversed EGCG-caused growth inhibition in IL-1-treated HASMCs. At the molecular level, EGCG treatment significantly activated nuclear factor erythroid-2-related factor (Nrf2) transcription activities. These results suggest that EGCG might serve as a complementary and alternative medicine in the treatment of these pathologies by inducing HO-1 expression and subsequently decreasing VSMC proliferation. Po-Len Liu, Jung-Tung Liu, Hsuan-Fu Kuo, Inn-Wen Chong, and Chong-Chao Hsieh Copyright © 2014 Po-Len Liu et al. All rights reserved. Jussara (Euterpe edulis Mart.) Supplementation during Pregnancy and Lactation Modulates the Gene and Protein Expression of Inflammation Biomarkers Induced by trans-Fatty Acids in the Colon of Offspring Sun, 07 Sep 2014 08:41:33 +0000 Maternal intake of trans-fatty acids (TFAs) in the perinatal period triggers a proinflammatory state in offspring. Anthocyanins contained in fruit are promising modulators of inflammation. This study investigated the effect of Jussara supplementation in the maternal diet on the proinflammatory state of the colon in offspring exposed to perinatal TFAs. On the first day of pregnancy rats were divided into four groups: control diet (C), control diet with 0.5% Jussara supplementation (CJ), diet enriched with hydrogenated vegetable fat, rich in TFAs (T), or T diet supplemented with 0.5% Jussara (TJ) during pregnancy and lactation. We showed that Jussara supplementation in maternal diet (CJ and TJ groups) reduced carcass lipid/protein ratios, serum lipids, glucose, IL-6, TNF-α, gene expression of IL-6R, TNF-αR (), TLR-4 (), and increase Lactobacillus spp. () in the colon of offspring compared to the T group. The IL-10 () and IL-10/TNF-α ratio () was higher in the CJ group than in the T group. The 0.5% Jussara supplementation reverses the adverse effects of perinatal TFAs, improving lipid profiles, glucose levels, body composition, and gut microbiota and reducing low-grade inflammation in the colon of 21-day-old offspring, and could contribute to reducing chronic disease development. Carina Almeida Morais, Lila Missae Oyama, Juliana Lopez de Oliveira, Márcia Carvalho Garcia, Veridiana Vera de Rosso, Laís Sousa Mendes Amigo, Claudia Maria Oller do Nascimento, and Luciana Pellegrini Pisani Copyright © 2014 Carina Almeida Morais et al. All rights reserved. The Inhibitory Effect of PIK-75 on Inflammatory Mediator Response Induced by Hydrogen Peroxide in Feline Esophageal Epithelial Cells Sun, 07 Sep 2014 08:05:06 +0000 Isoform-selective inhibitors of phosphoinositide 3-kinase (PI3K) activation have an anti-inflammatory effect by reducing proinflammatory cytokines. Cultured feline esophageal epithelial cells (EEC) of passages 3~4 were treated with hydrogen peroxide and PIK-75. The cell viability was measured by a MTT incorporation assay. The distribution of PI3K isoforms, p-Akt, IL-1β, and IL-8 was inferred from Western blots. The release of IL-6 was determined by ELISA. The cell morphology was not considerably different from nontreated cells if the cells were pretreated with PIK-75 and treated with 300 μM hydrogen peroxide. The density of p110α of PI3K was increased, but that of other types was not affected after the treatment with hydrogen peroxide. The density of p-Akt, when the cells were exposed to PIK-75 and hydrogen peroxide, was diminished dose dependently more than that of hydrogen peroxide treatment only. The decrease of p-Akt showed an inhibition of PI3K by PIK-75. PIK-75 dose dependently reduced the expression of IL-1β, IL-8, and the level of IL-6 compared with hydrogen peroxide treatment only. These results suggest evidence that p110α mediates esophageal inflammation and that PIK-75 has an anti-inflammatory effect by reducing proinflammatory cytokines on feline esophageal epithelial cultured cells. Jun Yeong Jeong, Yeon Joo Lee, Jeong Hoon Han, Sun Young Park, Kwang Woo Hwang, and Uy Dong Sohn Copyright © 2014 Jun Yeong Jeong et al. All rights reserved. Nucleotides Regulate Secretion of the Inflammatory Chemokine CCL2 from Human Macrophages and Monocytes Sun, 07 Sep 2014 06:45:09 +0000 CCL2 is an important inflammatory chemokine involved in monocyte recruitment to inflamed tissues. The extracellular nucleotide signalling molecules UTP and ATP acting via the P2Y2 receptor are known to induce CCL2 secretion in macrophages. We confirmed this in the human THP-1 monocytic cell line showing that UTP is as efficient as LPS at inducing CCL2 at early time points (2–6 hours). Expression and calcium mobilisation experiments confirmed the presence of functional P2Y2 receptors on THP-1 cells. UTP stimulation of human peripheral CD14+ monocytes showed low responses to LPS (4-hour stimulation) but a significant increase above background following 6 hours of treatment. The response to UTP in human monocytes was variable and required stimulation >6 hours. With such variability in response we looked for single nucleotide polymorphisms in P2RY2 that could affect the functional response. Sequencing of P2RY2 from THP-1 cells revealed the presence of a single nucleotide polymorphism altering amino acid 312 from arginine to serine (rs3741156). This polymorphism is relatively common at a frequency of 0.276 ( subjects). Finally, we investigated CCL2 secretion in response to LPS or UTP in human macrophages expressing 312Arg-P2Y2 or 312Ser-P2Y2 where only the latter exhibited significant UTP-induced CCL2 secretion ( donors per group). K. R. Higgins, W. Kovacevic, and L. Stokes Copyright © 2014 K. R. Higgins et al. All rights reserved. Pathogenic Roles of the Carotid Body Inflammation in Sleep Apnea Sun, 07 Sep 2014 05:45:08 +0000 Breathing difficulties in sleep are a hallmark of sleep-disordered breathing commonly observed in patients with sleep disorders. The pathophysiology of sleep apnea is in part due to an augmented activity of the carotid body chemoreflex. Arterial chemoreceptors in the carotid body are sensitive to inflammatory cytokines and immunogenic molecules in the circulation, because cytokine receptors are expressed in the carotid body in experimental animals and human. Intriguingly, proinflammatory cytokines are also locally produced and released in the carotid body. Also, there are significant increases in the expression of proinflammatory cytokines, cytokine receptors, and inflammatory mediators in the carotid body under hypoxic conditions, suggesting an inflammatory response of the carotid body. These upregulated cytokine signaling pathways could enhance the carotid chemoreceptor activity, leading to an overactivity of the chemoreflex adversely effecting breathing instability and autonomic imbalance. This review aims to summarize findings of the literature relevant to inflammation in the carotid body, with highlights on the pathophysiological impact in sleep apnea. It is concluded that local inflammation in the carotid body plays a pathogenic role in sleep apnea, which could potentially be a therapeutic target for the treatment of the pathophysiological consequence of sleep apnea. Man Lung Fung Copyright © 2014 Man Lung Fung. All rights reserved. Tumor Necrosis Factor-α-Induced Colitis Increases NADPH Oxidase 1 Expression, Oxidative Stress, and Neutrophil Recruitment in the Colon: Preventive Effect of Apocynin Thu, 04 Sep 2014 00:00:00 +0000 Reactive oxygen species- (ROS-) mediated injury has been implicated in several inflammatory disorders, including inflammatory bowel disease (IBD). NADPH oxidases (NOXs) are the major source of endogenous ROS. Here, we investigated the role of NOXs derived-ROS in a mouse model of colitis induced by the proinflammatory cytokine, tumor necrosis factor-α (TNF-α). Intraperitoneal injection of TNFα (10 μg · kg−1) induced an acute inflammation of the colon and a marked increase in expression of NADPH oxidase 1 (NOX1), a colon specific NADPH oxidase isoform. TNFα-induced colitis was also characterized by high production of keratinocyte-derived chemokine (KC) and mucosal infiltration of neutrophils, NOX2-expressing cells. Concomitantly, ROS production and lipid peroxidation were significantly enhanced while catalase activity and glutathione level were reduced indicating a redox imbalance in the colon. Furthermore, the redox-sensitive MAP kinases, ERK1/2 and p38 MAPK, were activated during TNFα-induced colitis. Pretreatment of mice with apocynin, an NADPH oxidase inhibitor with antioxidant properties, before TNFα challenge, prevented all these events. These data suggest that ROS derived from NADPH oxidases (mainly NOX1 and NOX2) and MAP kinase pathways could contribute to the induction and expansion of oxidative lesions characteristics of IBD and that apocynin could potentially be beneficial in IBD treatment. Souad Mouzaoui, Bahia Djerdjouri, Nesrine Makhezer, Yolande Kroviarski, Jamel El-Benna, and Pham My-Chan Dang Copyright © 2014 Souad Mouzaoui et al. All rights reserved.