Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Purine-Metabolizing Ectoenzymes Control IL-8 Production in Human Colon HT-29 Cells Wed, 23 Jul 2014 10:58:52 +0000 Interleukin-8 (IL-8) plays key roles in both chronic inflammatory diseases and tumor modulation. We previously observed that IL-8 secretion and function can be modulated by nucleotide (P2) receptors. Here we investigated whether IL-8 release by intestinal epithelial HT-29 cells, a cancer cell line, is modulated by extracellular nucleotide metabolism. We first identified that HT-29 cells regulated adenosine and adenine nucleotide concentration at their surface by the expression of the ectoenzymes NTPDase2, ecto-5′-nucleotidase, and adenylate kinase. The expression of the ectoenzymes was evaluated by RT-PCR, qPCR, and immunoblotting, and their activity was analyzed by RP-HPLC of the products and by detection of produced from the hydrolysis of ATP, ADP, and AMP. In response to poly (I:C), with or without ATP and/or ADP, HT-29 cells released IL-8 and this secretion was modulated by the presence of NTPDase2 and adenylate kinase. Taken together, these results demonstrate the presence of 3 ectoenzymes at the surface of HT-29 cells that control nucleotide levels and adenosine production (NTPDase2, ecto-5′-nucleotidase and adenylate kinase) and that P2 receptor-mediated signaling controls IL-8 release in HT-29 cells which is modulated by the presence of NTPDase2 and adenylate kinase. Fariborz Bahrami, Filip Kukulski, Joanna Lecka, Alain Tremblay, Julie Pelletier, Liliana Rockenbach, and Jean Sévigny Copyright © 2014 Fariborz Bahrami et al. All rights reserved. Serum Matrix Metalloproteinase-3 as a Noninvasive Biomarker of Histological Synovitis for Diagnosis of Rheumatoid Arthritis Wed, 23 Jul 2014 10:53:08 +0000 Objective. To explore the correlation between matrix metalloproteinase- (MMP-) 3 and histological synovitis in rheumatoid arthritis (RA). Methods. Serum MMP-3 of 62 patients with active RA was detected by ELISA. Serial synovial tissue sections from all RA patients, 13 osteoarthritis, and 10 orthopedic arthropathies patients were stained with hematoxylin and eosin and immunohistochemically for MMP-3, CD3, CD20, CD38, CD68, and CD15. Results. The percentage of lining MMP3+ cells was significantly higher in RA patients especially with high grade synovitis and it was significantly correlated with Krenn’s synovitis score and sublining inflammatory cells. Multivariate stepwise linear regression analysis revealed that the association of the percentage of lining MMP3+ cells with activation of synovial stroma, sublining CD68+ macrophages, and CD15+ neutrophils was stronger than other histological indicators. The percentage of lining MMP3+ cells was significantly correlated with serum MMP-3 in RA . Serum MMP-3 was higher in RA patients with high grade synovitis than that of low grade synovitis and significantly correlated with synovitis score and activation of synovial stroma subscore (all ). Conclusion. Serum MMP-3 may be an alternative noninvasive biomarker of histological synovitis and RA diagnosis. Jian-Da Ma, Jing-Jing Zhou, Dong-Hui Zheng, Le-Feng Chen, Ying-Qian Mo, Xiu-ning Wei, Li-Juan Yang, and Lie Dai Copyright © 2014 Jian-Da Ma et al. All rights reserved. Erratum to “Major Histocompatibility Complex I Mediates Immunological Tolerance of the Trophoblast during Pregnancy and May Mediate Rejection during Parturition” Wed, 23 Jul 2014 08:16:18 +0000 Anna Rapacz-Leonard, Małgorzata Dąbrowska, and Tomasz Janowski Copyright © 2014 Anna Rapacz-Leonard et al. All rights reserved. IL-10 Counteracts Proinflammatory Mediator Evoked Oxidative Stress in Caco-2 Cells Wed, 23 Jul 2014 06:50:26 +0000 Oxidative stress is thought to play a key role in the development of intestinal damage in intestinal inflammatory diseases. Several molecules are involved in the intestinal inflammation, either as pro- or anti-inflammatory factors; however, their effects on intestinal oxidative stress seem to be controversial. This work analyzes the contribution of pro- and anti-inflammatory molecules to the balance of oxidative damage in intestinal epithelial cells, as well as their effects on cellular antioxidant enzyme activity. With this purpose, the lipid and protein oxidation, together with the activity of catalase, superoxide dismutase, and glutathione peroxidase, were determined in the Caco-2 cells treated with serotonin, adenosine, melatonin, and TNFα, as proinflammatory factors, and IL-10, as an anti-inflammatory cytokine. The results have shown that all the proinflammatory factors assayed increased oxidative damage. In addition, these factors also inhibited the activity of antioxidant enzymes in the cells, except melatonin. In contrast, IL-10 did not alter these parameters but was able to reduce the prooxidant effects yielded by serotonin, adenosine, melatonin, or TNFα, in part by restoring the antioxidant enzymes activities. In summary, proinflammatory factors may induce oxidative damage in intestinal epithelial cells, whereas IL-10 seems to be able to restore the altered redox equilibrium in Caco-2 cells. Eva Latorre, Nyurky Matheus, Elena Layunta, Ana Isabel Alcalde, and José Emilio Mesonero Copyright © 2014 Eva Latorre et al. All rights reserved. Tumor Necrosis Factor Is a Therapeutic Target for Immunological Unbalance and Cardiac Abnormalities in Chronic Experimental Chagas’ Heart Disease Tue, 22 Jul 2014 12:17:06 +0000 Background. Chagas disease (CD) is characterized by parasite persistence and immunological unbalance favoring systemic inflammatory profile. Chronic chagasic cardiomyopathy, the main manifestation of CD, occurs in a TNF-enriched milieu and frequently progresses to heart failure. Aim of the Study. To challenge the hypothesis that TNF plays a key role in Trypanosoma cruzi-induced immune deregulation and cardiac abnormalities, we tested the effect of the anti-TNF antibody Infliximab in chronically T. cruzi-infected C57BL/6 mice, a model with immunological, electrical, and histopathological abnormalities resembling Chagas’ heart disease. Results. Infliximab therapy did not reactivate parasite but reshaped the immune response as reduced TNF mRNA expression in the cardiac tissue and plasma TNF and IFNγ levels; diminished the frequency of IL-17A+ but increased IL-10+ CD4+ T-cells; reduced TNF+ but augmented IL-10+ Ly6C+ and F4/80+ cells. Further, anti-TNF therapy decreased cytotoxic activity but preserved IFNγ-producing VNHRFTLV-specific CD8+ T-cells in spleen and reduced the number of perforin+ cells infiltrating the myocardium. Importantly, Infliximab reduced the frequency of mice afflicted by arrhythmias and second degree atrioventricular blocks and decreased fibronectin deposition in the cardiac tissue. Conclusions. Our data support that TNF is a crucial player in the pathogenesis of Chagas’ heart disease fueling immunological unbalance which contributes to cardiac abnormalities. Isabela Resende Pereira, Glaucia Vilar-Pereira, Andrea Alice Silva, Otacilio Cruz Moreira, Constança Britto, Ellen Diana Marinho Sarmento, and Joseli Lannes-Vieira Copyright © 2014 Isabela Resende Pereira et al. All rights reserved. The Role of Inflammation in the Pathogenesis of Macular Edema Secondary to Retinal Vascular Diseases Tue, 22 Jul 2014 09:28:11 +0000 Macular edema (ME) is a nonspecific sign of numerous retinal vascular diseases. This paper is an updated overview about the role of inflammatory processes in the genesis of both diabetic macular edema (DME) and ME secondary to retinal vein occlusion (RVO). We focus on the inflammatory mediators implicated, the effect of the different intravitreal therapies, the recruitment of leukocytes mediated by adhesion molecules, and the role of retinal Müller glial (RMG) cells. Francisco J. Ascaso, Valentín Huerva, and Andrzej Grzybowski Copyright © 2014 Francisco J. Ascaso et al. All rights reserved. Peritoneal Air Exposure Elicits an Intestinal Inflammation Resulting in Postoperative Ileus Tue, 22 Jul 2014 06:51:54 +0000 Background. The pathogenesis of postoperative ileus (POI) is complex. The present study was designed to investigate the effects of peritoneal air exposure on the POI intestinal inflammation and the underlying mechanism. Methods. Sprague-Dawley rats were randomized into five groups (6/group): the control group, the sham group, and three exposure groups with peritoneal air exposure for 1, 2, or 3 h. At 24 h after surgery, we analyzed the gastrointestinal transit, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, the myeloperoxidase activity, and the levels of TNF-α, IL-1β, IL-6, and IL-10 in the ileum and colon. The oxidant and antioxidant levels in the ileum and colon were analyzed by measuring malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC). Results. Peritoneal air exposure caused an air-exposure-time-dependent decrease in the gastrointestinal transit. The length of peritoneal air exposure is correlated with the severity of both systemic and intestinal inflammations and the increases in the levels of MDA, SOD, GSH-Px, and T-AOC. Conclusions. The length of peritoneal air exposure is proportional to the degree of intestinal paralysis and the severity of intestinal inflammation, which is linked to the oxidative stress response. Shanjun Tan, Wenkui Yu, Zhiliang Lin, Qiyi Chen, Jialiang Shi, Yi Dong, Kaipeng Duan, Xiaowu Bai, Lin Xu, Jieshou Li, and Ning Li Copyright © 2014 Shanjun Tan et al. All rights reserved. Rotenone Remarkably Attenuates Oxidative Stress, Inflammation, and Fibrosis in Chronic Obstructive Uropathy Tue, 22 Jul 2014 00:00:00 +0000 Mitochondrial abnormality has been shown in many kidney disease models. However, its role in the pathogenesis of chronic kidney diseases (CKDs) is still uncertain. In present study, a mitochondrial complex I inhibitor rotenone was applied to the mice subjected to unilateral ureteral obstruction (UUO). Following 7-days rotenone treatment, a remarkable attenuation of tubular injury was detected by PAS staining. In line with the improvement of kidney morphology, rotenone remarkably blunted fibrotic response as shown by downregulation of fibronectin (FN), plasminogen activator inhibitor-1 (PAI-1), collagen I, collagen III, and α-SMA, paralleled with a substantial decrease of TGF-β1. Meanwhile, the oxidative stress markers thiobarbituric acid-reactive substances (TBARS) and heme oxygenase 1 (HO-1) and inflammatory markers TNF-α, IL-1β, and ICAM-1 were markedly decreased. More importantly, the reduction of mitochondrial DNA copy number and mitochondrial NADH dehydrogenase subunit 1 (mtND1) expression in obstructed kidneys was moderately but significantly restored by rotenone, suggesting an amelioration of mitochondrial injury. Collectively, mitochondrial complex I inhibitor rotenone protected kidneys against obstructive injury possibly via inhibition of mitochondrial oxidative stress, inflammation, and fibrosis, suggesting an important role of mitochondrial dysfunction in the pathogenesis of obstructive kidney disease. Ying Sun, Yue Zhang, Daqiang Zhao, Guixia Ding, Songming Huang, Aihua Zhang, and Zhanjun Jia Copyright © 2014 Ying Sun et al. All rights reserved. Cell Death-Associated Molecular-Pattern Molecules: Inflammatory Signaling and Control Mon, 21 Jul 2014 10:49:40 +0000 Apoptosis, necroptosis, and pyroptosis are different cellular death programs characterized in organs and tissues as consequence of microbes infection, cell stress, injury, and chemotherapeutics exposure. Dying and death cells release a variety of self-proteins and bioactive chemicals originated from cytosol, nucleus, endoplasmic reticulum, and mitochondria. These endogenous factors are named cell death-associated molecular-pattern (CDAMP), damage-associated molecular-pattern (DAMP) molecules, and alarmins. Some of them cooperate or act as important initial or delayed inflammatory mediators upon binding to diverse membrane and cytosolic receptors coupled to signaling pathways for the activation of the inflammasome platforms and NF-κB multiprotein complexes. Current studies show that the nonprotein thiols and thiol-regulating enzymes as well as highly diffusible prooxidant reactive oxygen and nitrogen species released together in extracellular inflammatory milieu play essential role in controlling pro- and anti-inflammatory activities of CDAMP/DAMP and alarmins. Here, we provide an overview of these emerging concepts and mechanisms of triggering and maintenance of tissue inflammation under massive death of cells. Beatriz Sangiuliano, Nancy Marcela Pérez, Dayson F. Moreira, and José E. Belizário Copyright © 2014 Beatriz Sangiuliano et al. All rights reserved. IL-17 Genetic and Immunophenotypic Evaluation in Chronic Graft-versus-Host Disease Mon, 21 Jul 2014 00:00:00 +0000 Although interleukin-17 (IL-17) is a recently discovered cytokine associated with several autoimmune diseases, its role in the pathogenesis of chronic graft-versus-host disease (cGVHD) was not established yet. The objective of this study was to investigate the association of IL17A and IL17F genes polymorphisms and IL-17A and IL-17F levels with cGVHD. IL-17A expression was also investigated in CD4+ T cells of patients with systemic cGVHD. For Part I of the study, fifty-eight allo-HSCT recipients and donors were prospectively studied. Blood samples were obtained to determine IL17A and IL17F genes polymorphisms. Cytokines levels in blood and saliva were assessed by ELISA at days +35 and +100 after HSCT. In Part II, for the immunophenotypic evaluation, eight patients with systemic cGVHD were selected and the expression of IL-17A was evaluated. We found association between recipient AA genotype with systemic cGVHD. No association was observed between IL-17A levels and cGVHD. Lower IL-17A levels in the blood were associated with AA genotype. In flow cytometry analysis, decreased expression of IL-17A was observed in patients with cGVHD after stimulation. In conclusion, IL-17A may have an important role in the development of systemic cGVHD. Renata Gonçalves Resende, Jeane de Fátima Correia-Silva, Tarcília Aparecida Silva, Ulisses Eliezer Salomão, Luciano Marques-Silva, Érica Leandro Marciano Vieira, Walderez Ornelas Dutra, and Ricardo Santiago Gomez Copyright © 2014 Renata Gonçalves Resende et al. All rights reserved. Roles of Chronic Low-Grade Inflammation in the Development of Ectopic Fat Deposition Mon, 21 Jul 2014 00:00:00 +0000 Pattern of fat distribution is a major determinant for metabolic homeostasis. As a depot of energy, the storage of triglycerides in adipose tissue contributes to the normal fat distribution. Decreased capacity of fat storage in adipose tissue may result in ectopic fat deposition in nonadipose tissues such as liver, pancreas, and kidney. As a critical biomarker of metabolic complications, chronic low-grade inflammation may have the ability to affect the process of lipid accumulation and further lead to the disorder of fat distribution. In this review, we have collected the evidence linking inflammation with ectopic fat deposition to get a better understanding of the underlying mechanism, which may provide us with novel therapeutic strategies for metabolic disorders. Lulu Liu, Mei Mei, Shumin Yang, and Qifu Li Copyright © 2014 Lulu Liu et al. All rights reserved. Immunologic Biomarkers for Clinical and Therapeutic Management of Psoriasis Sun, 20 Jul 2014 08:54:57 +0000 Background. The therapeutic management of psoriasis includes conventional treatments as well as the new generation of highly effective TNF-α inhibitors. However, psoriasis has proven to be a complex therapeutic challenge and treatment failures are not uncommon. Thus, laboratory biomarkers of disease progression/therapeutic efficacy may greatly help in the clinical management of psoriasis. Aims. To identify laboratory biomarkers for clinical management and therapeutic monitoring of psoriasis. Methods. An observational study performed on 59 patients, presenting moderate to severe psoriasis, undergoing treatment with anti-TNF-α agents (etanercept, adalimumab, and infliximab). Soluble and cellular immune/inflammatory parameters were assessed at baseline and after 12 and 24 weeks of treatment. Results. Clinical efficacy was achieved in 88% of the subjects at 12 weeks, reaching 90% after 24 weeks. IL-6 and IL-22, which were elevated at baseline, were significantly reduced, in association with a significant decrease of CLA+ T cells and an increase of Treg lymphocytes. T, B, and NK cell subsets and T cell response to recall antigens did not show any evidence of immune suppression. Conclusions. Immune/inflammatory parameters including IL-6 and IL-22, CLA+ T cells, and Treg lymphocytes may prove to be valuable laboratory tools for the clinical and therapeutic monitoring of psoriasis. P. Cordiali-Fei, L. Bianchi, C. Bonifati, E. Trento, M. Ruzzetti, F. Francesconi, S. Bultrini, G. D’Agosto, V. Bordignon, V. Francavilla, A. Tripiciano, A. Chiricozzi, E. Campione, C. Cavallotti, A. Orlandi, E. Berardesca, A. Di Carlo, S. Chimenti, and F. Ensoli Copyright © 2014 P. Cordiali-Fei et al. All rights reserved. Hyperthermia Differently Affects Connexin43 Expression and Gap Junction Permeability in Skeletal Myoblasts and HeLa Cells Sun, 20 Jul 2014 08:39:10 +0000 Stress kinases can be activated by hyperthermia and modify the expression level and properties of membranous and intercellular channels. We examined the role of c-Jun NH2-terminal kinase (JNK) in hyperthermia-induced changes of connexin43 (Cx43) expression and permeability of Cx43 gap junctions (GJs) in the rabbit skeletal myoblasts (SkMs) and Cx43-EGFP transfected HeLa cells. Hyperthermia (42°C for 6 h) enhanced the activity of JNK and its target, the transcription factor c-Jun, in both SkMs and HeLa cells. In SkMs, hyperthermia caused a 3.2-fold increase in the total Cx43 protein level and enhanced the efficacy of GJ intercellular communication (GJIC). In striking contrast, hyperthermia reduced the total amount of Cx43 protein, the number of Cx43 channels in GJ plaques, the density of hemichannels in the cell membranes, and the efficiency of GJIC in HeLa cells. Both in SkMs and HeLa cells, these changes could be prevented by XG-102, a JNK inhibitor. In HeLa cells, the changes in Cx43 expression and GJIC under hyperthermic conditions were accompanied by JNK-dependent disorganization of actin cytoskeleton stress fibers while in SkMs, the actin cytoskeleton remained intact. These findings provide an attractive model to identify the regulatory players within signalosomes, which determine the cell-dependent outcomes of hyperthermia. Ieva Antanavičiūtė, Vida Mildažienė, Edgaras Stankevičius, Thomas Herdegen, and Vytenis Arvydas Skeberdis Copyright © 2014 Ieva Antanavičiūtė et al. All rights reserved. Antagonizing Arachidonic Acid-Derived Eicosanoids Reduces Inflammatory Th17 and Th1 Cell-Mediated Inflammation and Colitis Severity Thu, 17 Jul 2014 12:43:45 +0000 During colitis, activation of two inflammatory T cell subsets, Th17 and Th1 cells, promotes ongoing intestinal inflammatory responses. n-6 polyunsaturated fatty acid- (PUFA-) derived eicosanoids, such as prostaglandin E2 (PGE2), promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2 levels. We utilized two genetic mouse models, which differentially antagonize PGE2 levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Fat-1 mice contain the 3 desaturase gene from C. elegans and synthesize n-3 PUFA de novo, thereby reducing the biosynthesis of n-6 PUFA-derived eicosanoids. In contrast, Fads1 Null mice contain a disrupted desaturase gene and produce lower levels of n-6 PUFA-derived eicosanoids. Compared to Wt littermates, Fat-1 and Fads1 Null mice exhibited a similar colitic phenotype characterized by reduced colonic mucosal inflammatory eicosanoid levels and mRNA expression of Th17 cell markers (IL-17A, , and IL-23), decreased percentages of Th17 cells and, improved colon injury scores (). Thus, during colitis, similar outcomes were obtained in two genetically distinct models, both of which antagonize PGE2 levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation. Jennifer M. Monk, Harmony F. Turk, Yang-Yi Fan, Evelyn Callaway, Brad Weeks, Peiying Yang, David N. McMurray, and Robert S. Chapkin Copyright © 2014 Jennifer M. Monk et al. All rights reserved. Switching Off Key Signaling Survival Molecules to Switch On the Resolution of Inflammation Thu, 17 Jul 2014 12:20:32 +0000 Inflammation is a physiological response of the immune system to injury or infection but may become chronic. In general, inflammation is self-limiting and resolves by activating a termination program named resolution of inflammation. It has been argued that unresolved inflammation may be the basis of a variety of chronic inflammatory diseases. Resolution of inflammation is an active process that is fine-tuned by the production of proresolving mediators and the shutdown of intracellular signaling molecules associated with cytokine production and leukocyte survival. Apoptosis of leukocytes (especially granulocytes) is a key element in the resolution of inflammation and several signaling molecules are thought to be involved in this process. Here, we explore key signaling molecules and some mediators that are crucial regulators of leukocyte survival in vivo and that may be targeted for therapeutic purposes in the context of chronic inflammatory diseases. Denise Alves Perez, Juliana Priscila Vago, Rayssa Maciel Athayde, Alesandra Corte Reis, Mauro Martins Teixeira, Lirlândia Pires Sousa, and Vanessa Pinho Copyright © 2014 Denise Alves Perez et al. All rights reserved. The Effect of a Community-Based, Primary Health Care Exercise Program on Inflammatory Biomarkers and Hormone Levels Thu, 17 Jul 2014 12:18:39 +0000 The aim of this study was to analyze the impact of a community-based exercise program in primary care on inflammatory biomarkers and hormone levels. The 1-year quasiexperimental study involved 13 women (mean age = 56.8 ± 11.4 years) and it was developed in two basic health care units in Rio Claro City, Brazil. The physical exercise intervention was comprised of two, 60-minute sessions/week. The inflammatory biomarkers were measured at baseline, 6 months, and 1 year. Repeated measures ANOVA analyses indicated that the intervention was effective in reducing CRP and TNFα after 1 year compared to baseline and 6 months . There were no changes in IL10, IL6, and insulin after 1 year. However, leptin significantly increased at 1 year . The major finding of this study is that a community-based exercise program can result in a decrease or maintenance of inflammatory biomarkers after 1 year, and thus has the potential to be a viable public health approach for chronic disease prevention. Camila Bosquiero Papini, Priscila M. Nakamura, Lucas P. Zorzetto, Janice L. Thompson, Anna C. Phillips, and Eduardo Kokubun Copyright © 2014 Camila Bosquiero Papini et al. All rights reserved. The Wnt/β-Catenin Signaling Pathway Controls the Inflammatory Response in Infections Caused by Pathogenic Bacteria Thu, 17 Jul 2014 08:40:25 +0000 Innate immunity against pathogenic bacteria is critical to protect host cells from invasion and infection as well as to develop an appropriate adaptive immune response. During bacterial infection, different signaling transduction pathways control the expression of a wide range of genes that orchestrate a number of molecular and cellular events to eliminate the invading microorganisms and regulate inflammation. The inflammatory response must be tightly regulated because uncontrolled inflammation may lead to tissue injury. Among the many signaling pathways activated, the canonical Wnt/β-catenin has been recently shown to play an important role in the expression of several inflammatory molecules during bacterial infections. Our main goal in this review is to discuss the mechanism used by several pathogenic bacteria to modulate the inflammatory response through the Wnt/β-catenin signaling pathway. We think that a deep insight into the role of Wnt/β-catenin signaling in the inflammation may open new venues for biotechnological approaches designed to control bacterial infectious diseases. Octavio Silva-García, Juan J. Valdez-Alarcón, and Víctor M. Baizabal-Aguirre Copyright © 2014 Octavio Silva-García et al. All rights reserved. Intraperitoneal Infusion of Mesenchymal Stem/Stromal Cells Prevents Experimental Autoimmune Uveitis in Mice Thu, 17 Jul 2014 06:40:19 +0000 Autoimmune uveitis is one of the leading causes of blindness. We here investigated whether intraperitoneal administration of human mesenchymal stem/stromal cells (hMSCs) might prevent development of experimental autoimmune uveitis (EAU) in mice. Time course study showed that the number of IFN-γ- or IL-17-expressing CD4+ T cells was increased in draining lymph nodes (DLNs) on the postimmunization day 7 and decreased thereafter. The retinal structure was severely disrupted on day 21. An intraperitoneal injection of hMSCs at the time of immunization protected the retina from damage and suppressed the levels of proinflammatory cytokines in the eye. Analysis of DLNs on day 7 showed that hMSCs decreased the number of Th1 and Th17 cells. The hMSCs did not reduce the levels of IL-1β, IL-6, IL-12, and IL-23 which are the cytokines that drive Th1/Th17 differentiation. Also, hMSCs did not induce CD4+CD25+Foxp3+ cells. However, hMSCs increased the level of an immunoregulatory cytokine IL-10 and the population of IL-10-expressing B220+CD19+ cells. Together, data demonstrate that hMSCs attenuate EAU by suppressing Th1/Th17 cells and induce IL-10-expressing B220+CD19+ cells. Our results support suggestions that hMSCs may offer a therapy for autoimmune diseases mediated by Th1/Th17 responses. Joo Youn Oh, Tae Wan Kim, Hyun Jeong Jeong, Hyun Ju Lee, Jin Suk Ryu, Won Ryang Wee, Jang Won Heo, and Mee Kum Kim Copyright © 2014 Joo Youn Oh et al. All rights reserved. Macrophage Trafficking as Key Mediator of Adenine-Induced Kidney Injury Wed, 16 Jul 2014 12:05:17 +0000 Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. In this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Based on this perception, we evaluated the participation of macrophage recruitment in the development of TIN. Initially, we provided adenine-enriched food to WT and searched for macrophage presence and action in the kidney. Also, a group of animals were depleted of macrophages with the clodronate liposome while receiving adenine-enriched diet. We collected blood and renal tissue from these animals and renal function, inflammation, and fibrosis were evaluated. We observed higher expression of chemokines in the kidneys of adenine-fed mice and a substantial protection when macrophages were depleted. Then, we specifically investigated the role of some key chemokines, CCR5 and CCL3, in this TIN experimental model. Interestingly, CCR5 KO and CCL3 KO animals showed less renal dysfunction and a decreased proinflammatory profile. Furthermore, in those animals, there was less profibrotic signaling. In conclusion, we can suggest that macrophage infiltration is important for the onset of renal injury in the adenine-induced TIN. Matheus Correa-Costa, Tárcio Teodoro Braga, Raphael José Ferreira Felizardo, Vinícius Andrade-Oliveira, Katia Regina Perez, Iolanda Midea Cuccovia, Meire Ioshie Hiyane, João Santana da Silva, and Niels Olsen Saraiva Câmara Copyright © 2014 Matheus Correa-Costa et al. All rights reserved. Intestinal Mucosal Barrier Is Injured by BMP2/4 via Activation of NF-B Signals after Ischemic Reperfusion Wed, 16 Jul 2014 10:01:56 +0000 Intestinal ischemic reperfusion (I/R) can cause dysfunction of the intestinal mucosal barrier; however, the mechanism of the intestinal mucosal barrier dysfunction caused by I/R remains unclear. In this study, using intestinal epithelial cells under anaerobic cultivation and an in vivo rat intestinal I/R model, we found that hypoxia and I/R increased the expression of BMP2/4 and upregulated BMP type Ia receptor and BMP type II receptor expression. We also found that exogenous BMP2/4 can activate the ERK and AKT signaling pathways in rat small intestine (IEC-6) cells, thereby activating NF-B signaling, which leads to increased levels of inflammatory factors, such as TNF- and IL-6. Furthermore, recombinant BMP2/4 decreased the expression of the tight junction protein occludin via the activation of the NF-B pathway; these effects were abolished by treatment with the BMP-specific antagonist noggin or the NF-B inhibitor pyrrolidine dithiocarbamate (PDTC). All these factors can destroy the intestinal mucosal barrier, thereby leading to weaker barrier function. On the basis of these data, we conclude that BMP2/4 may act as the pathogenic basis for intestinal mucosal barrier dysfunction when the intestines suffer an I/R injury. Our results provide background for the development pharmacologic interventions in the management of I/R injury. Kang Chen, Wei Xie, Binyu Luo, Weidong Xiao, Daniel H. Teitelbaum, Hua Yang, Kebin Zhang, and Chaojun Zhang Copyright © 2014 Kang Chen et al. All rights reserved. Role of Microglia Adenosine A2A Receptors in Retinal and Brain Neurodegenerative Diseases Wed, 16 Jul 2014 09:18:53 +0000 Neuroinflammation mediated by microglial cells in the brain has been commonly associated with neurodegenerative diseases. Whether this microglia-mediated neuroinflammation is cause or consequence of neurodegeneration is still a matter of controversy. However, it is unequivocal that chronic neuroinflammation plays a role in disease progression and halting that process represents a potential therapeutic strategy. The neuromodulator adenosine emerges as a promising targeting candidate based on its ability to regulate microglial proliferation, chemotaxis, and reactivity through the activation of its G protein coupled receptor (). This is in striking agreement with the ability of blockade to control several brain diseases. Retinal degenerative diseases have been also associated with microglia-mediated neuroinflammation, but the role of has been scarcely explored. This review aims to compare inflammatory features of Parkinson’s and Alzheimer’s diseases with glaucoma and diabetic retinopathy, discussing the therapeutic potential of in these degenerative conditions. Ana R. Santiago, Filipa I. Baptista, Paulo F. Santos, Gonçalo Cristóvão, António F. Ambrósio, Rodrigo A. Cunha, and Catarina A. Gomes Copyright © 2014 Ana R. Santiago et al. All rights reserved. Oral Administration of Herbal Mixture Extract Inhibits 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in BALB/c Mice Wed, 16 Jul 2014 07:23:04 +0000 CP001 is four traditional herbal medicine mixtures with anti-inflammatory properties. In this study, we investigated the effect of oral administration of CP001 ethanol extract on the 2,4-dinitrochlorobenzene- (DNCB-) induced AD mouse models. For that purpose, we observed the effects of oral administration of CP001 on skin inflammatory cell infiltration, skin mast cells, production of serum IgE, and expression of Th2 cytokine mRNA in the AD skin lesions of DNCB treated BALB/c mice. Histological analyses demonstrated that CP001 decreased dermis and epidermis thickening as well as dermal infiltration induced by inflammatory cells. In addition, CP001 decreased mast cell infiltration in count as well as dermal infiltration induced by inflammatory cells. In the skin lesions, mRNA expression of interleukin- (IL-) 4 and IL-13 was inhibited by CP001. CP001 also reduced the production of IgE level in mouse plasma. In addition, we investigated the effect of CP001 on the inflammatory allergic reaction using human mast cells (HMC-1). In HMC-1, cytokine production and mRNA levels of IL-4, IL-13, IL-6, and IL-8 were suppressed by CP001. Taken together, our results showed that oral administration of CP001 exerts beneficial effects in AD symptoms, suggesting that CP001 might be a useful candidate for the treatment of AD. Soon Re Kim, Han-Seok Choi, Hye Sook Seo, Jin Mo Ku, Se Hyang Hong, Hye Hyun Yoo, Yong Cheol Shin, and Seong-Gyu Ko Copyright © 2014 Soon Re Kim et al. All rights reserved. Endocan Levels in Peripheral Blood Predict Outcomes of Acute Respiratory Distress Syndrome Wed, 16 Jul 2014 00:00:00 +0000 Purpose. To investigate the prognostic significance of endocan, compared with procalcitonin (PCT), C-reactive protein (CRP),white blood cells (WBC), neutrophils (N), and clinical severity scores in patients with ARDS. Methods. A total of 42 patients with ARDS were initially enrolled, and there were 20 nonsurvivors and 22 survivors based on hospital mortality. Plasma levels of biomarkers were measured and the acute physiology and chronic health evaluation II (APACHE II) was calculated on day 1 after the patient met the defining criteria of ARDS. Results. Endocan levels significantly correlated with the APACHE II score in the ARDS group (, , ). Of 42 individuals with ARDS, 20 were dead, and endocan was significantly higher in nonsurvivors than in survivors (median (IQR) 5.01 (2.98–8.44) versus 3.01 (2.36–4.36) ng/mL, ). According to the results of the ROC-curve analysis and COX proportional hazards models, endocan can predict mortality of ARDS independently with a hazard ratio of 1.374 (95% CI, 1.150–1.641) and an area of receiver operator characteristic curve (AUROC) of 0.715 (). Moreover, endocan can predict the multiple-organ dysfunction of ARDS. Conclusion. Endocan is a promising biomarker to predict the disease severity and mortality in patients with ARDS. Ling Tang, Ying Zhao, Daoxin Wang, Wang Deng, Changyi Li, Qi Li, Shicong Huang, and Chang Shu Copyright © 2014 Ling Tang et al. All rights reserved. Interferons and Interferon Regulatory Factors in Malaria Tue, 15 Jul 2014 12:01:41 +0000 Malaria is one of the most serious infectious diseases in humans and responsible for approximately 500 million clinical cases and 500 thousand deaths annually. Acquired adaptive immune responses control parasite replication and infection-induced pathologies. Most infections are clinically silent which reflects on the ability of adaptive immune mechanisms to prevent the disease. However, a minority of these can become severe and life-threatening, manifesting a range of overlapping syndromes of complex origins which could be induced by uncontrolled immune responses. Major players of the innate and adaptive responses are interferons. Here, we review their roles and the signaling pathways involved in their production and protection against infection and induced immunopathologies. Sin Yee Gun, Carla Claser, Kevin Shyong Wei Tan, and Laurent Rénia Copyright © 2014 Sin Yee Gun et al. All rights reserved. YKL-40 as a Novel Factor Associated with Inflammation and Catabolic Mechanisms in Osteoarthritic Joints Tue, 15 Jul 2014 12:00:22 +0000 YKL-40 is associated with tissue injury and inflammation, and consequently to diseases in which these mechanisms lead to tissue degradation, for example, asthma and rheumatoid arthritis. The purpose of the present study was to investigate if YKL-40 is also a significant factor in osteoarthritis (OA) by assessing associations of YKL-40 with mediators related to the pathogenesis of OA: cartilage destructing matrix metalloproteinases (MMPs) and proinflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17). Cartilage, synovial fluid (SF), and plasma samples were obtained from 100 OA patients undergoing total knee replacement surgery. SF levels of YKL-40 (1027.9 ± 78.3 ng/mL) were considerably higher than plasma levels (67.2 ± 4.5 ng/mL) and correlated with YKL-40 released from cartilage samples obtained from the same patients (, ), indicating that YKL-40 is produced by OA cartilage. Interestingly, YKL-40 concentrations in OA SF correlated positively with MMP-1 (, ), MMP-3 (, ), IL-6 (, ), and IL-17 (, ) levels. Moreover, IL-6 and IL-17 enhanced YKL-40 production in human primary chondrocyte cultures. The present study introduces YKL-40 as a cartilage-derived factor associated with mediators of inflammation and cartilage destruction involved in the pathogenesis of OA. Tuija Väänänen, Anna Koskinen, Erja-Leena Paukkeri, Mari Hämäläinen, Teemu Moilanen, Eeva Moilanen, and Katriina Vuolteenaho Copyright © 2014 Tuija Väänänen et al. All rights reserved. Circumsporozoite Protein-Specific -Restricted CD8+ T Cells Mediate Protective Antimalaria Immunity in Sporozoite-Immunized MHC-I- Transgenic Mice Tue, 15 Jul 2014 09:39:35 +0000 Although the roles of CD8+ T cells and a major preerythrocytic antigen, the circumsporozoite (CS) protein, in contributing protective antimalaria immunity induced by radiation-attenuated sporozoites, have been shown by a number of studies, the extent to which these players contribute to antimalaria immunity is still unknown. To address this question, we have generated C57BL/6 (B6) transgenic (Tg) mice, expressing molecules under the MHC-I promoter, called MHC-I--Tg mice. In this study, we first determined that a single immunizing dose of IrPySpz induced a significant level of antimalaria protective immunity in MHC-I--Tg mice but not in B6 mice. Then, by depleting various T-cell subsets in vivo, we determined that CD8+ T cells are the main mediator of the protective immunity induced by IrPySpz. Furthermore, when we immunized (MHC-I--Tg × CS-Tg) F1 mice with IrPySpz after crossing MHC-I--Tg mice with PyCS-transgenic mice (CS-Tg), which are unable to mount PyCS-specific immunity, we found that IrPySpz immunization failed to induce protective antimalaria immunity in (MHC-I--Tg × CS-Tg) F1 mice, thus indicating the absence of PyCS antigen-dependent immunity in these mice. These results indicate that protective antimalaria immunity induced by IrPySpz in MHC-I--Tg mice is mediated by CS protein-specific, -restricted CD8+ T cells. Jing Huang, Tiffany Tsao, Min Zhang, and Moriya Tsuji Copyright © 2014 Jing Huang et al. All rights reserved. Untangling the Web of Systemic Autoinflammatory Diseases Tue, 15 Jul 2014 08:00:58 +0000 The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment. Donato Rigante, Giuseppe Lopalco, Antonio Vitale, Orso Maria Lucherini, Francesco Caso, Caterina De Clemente, Francesco Molinaro, Mario Messina, Luisa Costa, Mariangela Atteno, Franco Laghi-Pasini, Giovanni Lapadula, Mauro Galeazzi, Florenzo Iannone, and Luca Cantarini Copyright © 2014 Donato Rigante et al. All rights reserved. Relationship between Early Inflammatory Response and Clinical Evolution of the Severe Multiorgan Failure in Mechanical Circulatory Support-Treated Patients Mon, 14 Jul 2014 14:21:52 +0000 Background. The mechanical circulatory support (MCS) is an effective treatment in critically ill patients with end-stage heart failure (ESHF) that, however, may cause a severe multiorgan failure syndrome (MOFS) in these subjects. The impact of altered inflammatory response, associated to MOFS, on clinical evolution of MCS postimplantation patients has not been yet clarified. Methods. Circulating cytokines, adhesion molecules, and a marker of monocyte activation (neopterin) were determined in 53 MCS-treated patients, at preimplant and until 2 weeks. MOFS was evaluated by total sequential organ failure assessment score (tSOFA). Results. During MCS treatment, 32 patients experienced moderate MOFS (tSOFA < 11; A group), while 21 patients experienced severe MOFS (tSOFA ≥ 11) with favorable (B group) or adverse (, C group) outcomes. At preimplant, higher values of left ventricular ejection fraction (LVEF) and estimated glomerular filtration rate (eGFR) were the only parameter independently associated with A group. In C group, during the first postoperative week, high levels of interleukin-8 (IL-8) and tumor necrosis factor (TNF)-α, and an increase of neopterin and adhesion molecules, precede tSOFA worsening and exitus. Conclusions. The MCS patients of C group show an excessive release to IL-8 and TNF-α, and monocyte-endothelial activation after surgery, that might contribute to the unfavourable evolution of severe MOFS. Raffaele Caruso, Jonica Campolo, Alessandro Verde, Luca Botta, Lorena Cozzi, Marina Parolini, Filippo Milazzo, Sandra Nonini, Luigi Martinelli, Roberto Paino, Paolo Marraccini, and Maria Frigerio Copyright © 2014 Raffaele Caruso et al. All rights reserved. Purinergic Receptors in Ocular Inflammation Mon, 14 Jul 2014 11:30:01 +0000 Inflammation is a complex process that implies the interaction between cells and molecular mediators, which, when not properly “tuned,” can lead to disease. When inflammation affects the eye, it can produce severe disorders affecting the superficial and internal parts of the visual organ. The nucleoside adenosine and nucleotides including adenine mononucleotides like ADP and ATP and dinucleotides such as P1,P4-diadenosine tetraphosphate (Ap4A), and P1,P5-diadenosine pentaphosphate (Ap5A) are present in different ocular locations and therefore they may contribute/modulate inflammatory processes. Adenosine receptors, in particular adenosine receptors, present anti-inflammatory action in acute and chronic retinal inflammation. Regarding the A3 receptor, selective agonists like N6-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine (CF101) have been used for the treatment of inflammatory ophthalmic diseases such as dry eye and uveoretinitis. Sideways, diverse stimuli (sensory stimulation, large intraocular pressure increases) can produce a release of ATP from ocular sensory innervation or after injury to ocular tissues. Then, ATP will activate purinergic P2 receptors present in sensory nerve endings, the iris, the ciliary body, or other tissues surrounding the anterior chamber of the eye to produce uveitis/endophthalmitis. In summary, adenosine and nucleotides can activate receptors in ocular structures susceptible to suffer from inflammatory processes. This involvement suggests the possible use of purinergic agonists and antagonists as therapeutic targets for ocular inflammation. Ana Guzman-Aranguez, Xavier Gasull, Yolanda Diebold, and Jesús Pintor Copyright © 2014 Ana Guzman-Aranguez et al. All rights reserved. Opposing Roles of Leptin and Ghrelin in the Equine Corpus Luteum Regulation: An In Vitro Study Mon, 14 Jul 2014 00:00:00 +0000 Metabolic hormones have been associated with reproductive function modulation. Thus, the aim of this study was: (i) to characterize the immunolocalization, mRNA and protein levels of leptin (LEP), Ghrelin (GHR) and respective receptors LEPR and Ghr-R1A, throughout luteal phase; and (ii) to evaluate the role of LEP and GHR on progesterone (P4), prostaglandin (PG) E2 and PGF2α, nitric oxide (nitrite), tumor necrosis factor-α (TNF); macrophage migration inhibitory factor (MIF) secretion, and on angiogenic activity (BAEC proliferation), in equine corpus luteum (CL) from early and mid-luteal stages. LEPR expression was decreased in late CL, while GHR/Ghr-R1A system was increased in the same stage. Regarding secretory activity, GHR decreased P4 in early CL, but increased PGF2α, nitrite and TNF in mid CL. Conversely, LEP increased P4, PGE2, angiogenic activity, MIF, TNF and nitrite during early CL, in a dose-dependent manner. The in vitro effect of LEP on secretory activity was reverted by GHR, when both factors acted together. The present results evidence the presence of LEP and GHR systems in the equine CL. Moreover, we suggest that LEP and GHR play opposing roles in equine CL regulation, with LEP supporting luteal establishment and GHR promoting luteal regression. Finally, a dose-dependent luteotrophic effect of LEP was demonstrated. António Galvão, Angela Tramontano, Maria Rosa Rebordão, Ana Amaral, Pedro Pinto Bravo, Anna Szóstek, Dariusz Skarzynski, Antonio Mollo, and Graça Ferreira-Dias Copyright © 2014 António Galvão et al. All rights reserved.