Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. The Effects of Amphiregulin Induced MMP-13 Production in Human Osteoarthritis Synovial Fibroblast Thu, 24 Jul 2014 18:42:27 +0000 Osteoarthritis (OA) belongs to a group of degenerative diseases. Synovial inflammation, cartilage abrasion, and subchondral sclerosis are characteristics of OA. Researchers do not fully understand the exact etiology of OA. However, matrix metalloproteinases (MMPs), which are responsible for cartilage matrix degradation, play a pivotal role in the progression of OA. Amphiregulin (AREG) binds to the EGF receptor (EGFR) and activates downstream proteins. AREG is involved in a variety of pathological processes, such as the development of tumors, inflammatory diseases, and rheumatoid arthritis. However, the relationship between AREG and MMP-13 in OA synovial fibroblasts (SFs) remains unclear. We investigated the signaling pathway involved in AREG-induced MMP-13 production in SFs. AREG caused MMP-13 production in a concentration- and time-dependent manner. The results of using pharmacological inhibitors and EGFR siRNA to block EGFR revealed that the EGFR receptor was involved in the AREG-mediated upregulation of MMP-13. AREG-mediated MMP-13 production was attenuated by PI3K and Akt inhibitors. The stimulation of cells by using AREG activated p65 phosphorylation and p65 translocation from the cytosol to the nucleus. Our results provide evidence that AREG acts through the EGFR and activates PI3K, Akt, and finally NF-kappaB on the MMP-13 promoter, thus contributing to cartilage destruction during osteoarthritis. Yi-Te Chen, Chun-Han Hou, Sheng-Mou Hou, and Ju-Fang Liu Copyright © 2014 Yi-Te Chen et al. All rights reserved. Auricular Electroacupuncture Reduced Inflammation-Related Epilepsy Accompanied by Altered TRPA1, pPKCα, pPKCε, and pERk1/2 Signaling Pathways in Kainic Acid-Treated Rats Thu, 24 Jul 2014 18:41:12 +0000 Background. Inflammation is often considered to play a crucial role in epilepsy by affecting iron status and metabolism. In this study, we investigated the curative effect of auricular acupuncture and somatic acupuncture on kainic acid- (KA-) induced epilepsy in rats. Methods. We established an epileptic seizure model in rats by KA (12 mg, ip). The 2 Hz electroacupuncture (EA) was applied at auricular and applied at Zusanli and Shangjuxu (ST36-ST37) acupoints for 20 min for 3 days/week for 6 weeks beginning on the day following the KA injection. Results. The electrophysiological results indicated that neuron overexcitation occurred in the KA-treated rats. This phenomenon could be reversed among either the auricular EA or ST36-ST37 EA treatment, but not in the sham-control rats. The Western blot results revealed that TRPA1, but not TRPV4, was upregulated by injecting KA and could be attenuated by administering auricular or ST36-ST37 EA, but not in the sham group. In addition, potentiation of TRPA1 was accompanied by increased PKCα and reduced PKCε. Furthermore, pERK1/2, which is indicated in inflammation, was also increased by KA. Furthermore, the aforementioned mechanisms could be reversed by administering auricular EA and could be partially reversed by ST36-ST37 EA. Conclusions. These results indicate a novel mechanism for treating inflammation-associated epilepsy and can be translated into clinical therapy. Yi-Wen Lin and Ching-Liang Hsieh Copyright © 2014 Yi-Wen Lin and Ching-Liang Hsieh. All rights reserved. Association between Peak Neutrophil Count, Clopidogrel Loading Dose, and Left Ventricular Systolic Function in Patients with Primary Percutaneous Coronary Intervention Thu, 24 Jul 2014 11:54:39 +0000 Inflammation plays an important role in plaque development and left ventricular remodeling during acute myocardial infarction (AMI). Clopidogrel may exhibit some anti-inflammatory properties and high loading dose of clopidogrel results in improved clinical outcomes in patients with AMI. 357 patients who received successful primary percutaneous coronary intervention from January 2008 to March 2011 in Peking University Third Hospital were included in this study. Different loading dose of clopidogrel (300 mg, 450 mg, or 600 mg) was given at the discretion of the clinician. Neutrophils reached their peak values on the first day after AMI. Higher levels of peak neutrophil and lower left ventricular ejection fraction (LVEF) were found in patients of low clopidogrel loading dose group (300 mg or 450 mg). After adjusting for the related confounders, a logistic regression model showed that low clopidogrel loading dose remained an independent predictor of low LVEF (LVEF ≤ 50%) [OR: 1.97, 95% CI: 1.03–3.79, P = 0.04]. Low clopidogrel loading dose was associated with higher peak neutrophil count and poor left ventricular systolic function, suggesting an important role of clopidogrel loading dose in the improvement of left ventricular function and high loading dose may exhibit better anti-inflammatory properties. Xinyu Wang, Haiyi Yu, Zhaoping Li, Liuning Li, Youyi Zhang, and Wei Gao Copyright © 2014 Xinyu Wang et al. All rights reserved. Palmitoleic Acid (N-7) Attenuates the Immunometabolic Disturbances Caused by a High-Fat Diet Independently of PPARα Thu, 24 Jul 2014 11:30:57 +0000 Palmitoleic acid (PMA) has anti-inflammatory and antidiabetic activities. Here we tested whether these effects of PMA on glucose homeostasis and liver inflammation, in mice fed with high-fat diet (HFD), are PPAR- dependent. C57BL6 wild-type (WT) and PPAR--knockout (KO) mice fed with a standard diet (SD) or HFD for 12 weeks were treated after the 10th week with oleic acid (OLA, 300 mg/kg of b.w.) or PMA 300 mg/kg of b.w. Steatosis induced by HFD was associated with liver inflammation only in the KO mice, as shown by the increased hepatic levels of IL1-beta, IL-12, and TNF-; however, the HFD increased the expression of TLR4 and decreased the expression of IL1-Ra in both genotypes. Treatment with palmitoleate markedly attenuated the insulin resistance induced by the HFD, increased glucose uptake and incorporation into muscle in vitro, reduced the serum levels of AST in WT mice, decreased the hepatic levels of IL1-beta and IL-12 in KO mice, reduced the expression of TLR-4 and increased the expression of IL-1Ra in WT mice, and reduced the phosphorylation of NF 𝜅B (p65) in the livers of KO mice. We conclude that palmitoleate attenuates diet-induced insulin resistance, liver inflammation, and damage through mechanisms that do not depend on PPAR-. Camila O. Souza, Alexandre A. S. Teixeira, Edson A. Lima, Helena A. P. Batatinha, Lara M. Gomes, Milena Carvalho-Silva, Isabella T. Mota, Emilio L. Streck, Sandro M. Hirabara, and José C. Rosa Neto Copyright © 2014 Camila O. Souza et al. All rights reserved. Myocardial Gene Expression of T-bet, GATA-3, Ror-t, FoxP3, and Hallmark Cytokines in Chronic Chagas Disease Cardiomyopathy: An Essentially Unopposed TH1-Type Response Thu, 24 Jul 2014 09:56:26 +0000 Background. Chronic Chagas disease cardiomyopathy (CCC), a late consequence of Trypanosoma cruzi infection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC). Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (1/2/17/Treg) in CCC, NIC, and heart donor myocardial samples. Methods and Results. Quantitative PCR showed markedly upregulated expression of IFN-γ and transcription factor T-bet, and minor increases of GATA-3; FoxP3 and CTLA-4; IL-17 and IL-18 in CCC as compared with NIC samples. Conversely, cytokines expressed by 2 cells (IL-4, IL-5, and IL-13) or associated with Treg (TGF-β and IL-10) were not upregulated in CCC myocardium. Expression of 1-related genes such as T-bet, IFN-γ, and IL-18 correlated with ventricular dilation, FoxP3, and CTLA-4. Conclusions. Results are consistent with a strong local 1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+ Treg cell population, which is unable to completely curb IFN-γ production in CCC myocardium, therefore fueling inflammation. Luciana Gabriel Nogueira, Ronaldo Honorato Barros Santos, Alfredo Inácio Fiorelli, Eliane Conti Mairena, Luiz Alberto Benvenuti, Edimar Alcides Bocchi, Noedir Antonio Stolf, Jorge Kalil, and Edecio Cunha-Neto Copyright © 2014 Luciana Gabriel Nogueira et al. All rights reserved. Chitosan Oligosaccharides Attenuate Ocular Inflammation in Rats with Experimental Autoimmune Anterior Uveitis Thu, 24 Jul 2014 09:31:58 +0000 We investigated the protective effects and mechanisms of chitosan oligosaccharides (COS) on experimental autoimmune anterior uveitis (EAAU) in rats. EAAU was induced in Lewis rats by footpad and intraperitoneal injections of melanin-associated antigen. The rats received intraperitoneal injections of low-dose (5 mg/kg) or high-dose (10 mg/kg) COS or PBS daily after the immunization. The effects of COS were evaluated by determining the clinical scores and the morphology of the iris/ciliary body (ICB). The expression of inflammatory mediators was evaluated using western blot, immunofluorescence, and ELISA. Treatment with COS significantly attenuated the clinical scores and the leukocyte infiltration in the ICB in a dose-dependent manner. COS effectively reduced the expression of inflammatory mediators (TNF-α, iNOS, MCP-1, RANTES, fractalkine, and ICAM-1). Moreover, COS decreased the IκB degradation and p65 presence in the ICB, which resulted in the inhibition of NF-κB/DNA binding activity. In an in vitro study, sensitized spleen-derived lymphocytes of the COS-treated group showed less chemotaxis toward their aqueous humor and decreased secretion of the above inflammatory mediators in the culture media. COS treated EAAU by inhibiting the activation of NF-κB and reducing the expression of inflammatory mediators. COS might be a potential treatment for acute anterior uveitis. I-Mo Fang, Chang-Hao Yang, and Chung-May Yang Copyright © 2014 I-Mo Fang et al. All rights reserved. Interleukin-17 Gene Polymorphisms Contribute to Cancer Risk Thu, 24 Jul 2014 07:16:58 +0000 Epidemiological studies have suggested that interleukin-17 (IL-17) polymorphisms are associated with cancer risk. However, the results of these studies are inconsistent. Therefore, we performed a meta-analysis to obtain a precise conclusion. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association of the IL-17A rs2275913GA and IL-17F rs763780TC polymorphisms with cancer risk. Publication bias and sensitivity analyses were performed to ensure the statistical power. Overall, 10 relevant case-control studies involving 4,516 cases and 5,645 controls were included. The pooled ORs with 95% CIs indicated that the IL-17A rs2275913GA polymorphism was significantly associated with increased cancer risk (for A versus G: OR = 1.28, 95% CI: 1.16–1.41, , %; for GA versus GG: OR = 1.12, 95% CI: 1.02–1.23, P = 0.015, %; for AA versus GG: OR = 1.71, 95% CI: 1.38–2.41, , %; for GA + AA versus GG: OR = 1.23, 95% CI: 1.13–1.34, , %; for AA versus GG + GA: OR = 1.62, 95% CI: 1.27–2.07, , %). Succeeding analysis of HWE and stratified analysis of gastric cancer and the Asian (and Chinese) population revealed similar results. The IL-17F rs763780T>C polymorphism was also significantly associated with gastric cancer development. Overall, the present meta-analysis suggests that IL-17 polymorphisms increase the risk of developing cancer, particularly gastric cancer, in the Asian (and Chinese) population. Yu-Ming Niu, Hua Yuan, and Yu Zhou Copyright © 2014 Yu-Ming Niu et al. All rights reserved. Cytokines and Chemokines: Disease Models, Mechanisms, and Therapies Thu, 24 Jul 2014 07:14:56 +0000 Salahuddin Ahmed, Charles J. Malemud, Alisa E. Koch, Mohammad Athar, and Dennis D. Taub Copyright © 2014 Salahuddin Ahmed et al. All rights reserved. Assessment of the E-Selectin rs5361 (561A>C) Polymorphism and Soluble Protein Concentration in Acute Coronary Syndrome: Association with Circulating Levels Thu, 24 Jul 2014 00:00:00 +0000 Introduction. The acute coronary syndrome (ACS) is a complex disease where genetic and environmental factors are involved. E-selectin gene is a candidate for ACS progression due to its contribution in the inflammatory process and endothelial function. The rs5361 (561A>C) polymorphism in the E-selectin gene has been linked to changes in gene expression, affinity for its receptor, and plasmatic levels; therefore it is associated with an increased risk of cardiovascular disease. The aim of this study was to determine the association of the rs5361 polymorphism with ACS and to measure serum levels of soluble E-selectin (sE-selectin). Materials and Methods. 283 ACS patients and 205 healthy subjects (HS) from Western Mexico were included. The polymerase chain reaction-restriction fragment length polymorphism was used to determine the rs5361 polymorphism. The sE-selectin levels were measured by enzyme-linked immunosorbent assay. Results. Neither genotype nor allele frequencies of the rs5361 polymorphism showed statistical differences between groups. The sE-selectin levels were significantly higher in ACS patients compared to HS (54.58 versus 40.41 ng/ml, . The C allele had no effect on sE-selectin levels. Conclusions. The rs5361 E-selectin gene polymorphism is not a susceptibility marker for ACS in Western Mexico population. However, sE-selectin may be a biological marker of ACS. Elena Sandoval-Pinto, Jorge Ramon Padilla-Gutiérrez, Emmanuel Valdes-Alvarado, Ilian Janet García-González, Angelica Valdez-Haro, Jose Francisco Muñoz-Valle, Hector Enrique Flores-Salinas, Fernando Rivas, and Yeminia Valle Copyright © 2014 Elena Sandoval-Pinto et al. All rights reserved. Sphingosine-1-phosphate/S1P Receptors Signaling Modulates Cell Migration in Human Bone Marrow-Derived Mesenchymal Stem Cells Wed, 23 Jul 2014 13:41:16 +0000 The recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) to damaged tissues and sites of inflammation is an essential step for clinical therapy. However, the signals regulating the motility of these cells are still not fully understood. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is known to have a variety of biological effects on various cells. Here, we investigated the roles of S1P and S1P receptors (S1PRs) in migration of human BMSCs. We found that S1P exerted a powerful migratory action on human BMSCs. Moreover, by employing RNA interference technology and pharmacological tools, we demonstrated that S1PR1 and S1PR3 are responsible for S1P-induced migration of human BMSCs. In contrast, S1PR2 mediates the inhibition of migration. Additionally, we explored the downstream signaling pathway of the S1P/S1PRs axis and found that activation of S1PR1 or S1PR3 increased migration of human BMSCs through a /extracellular regulated protein kinases 1/2- (ERK1/2-) dependent pathway, whereas activation of S1PR2 decreased migration through the Rho/Rho-associated protein kinase (ROCK) pathway. In conclusion, we reveal that the S1P/S1PRs signaling axis regulates the migration of human BMSCs via a dual-directional mechanism. Thus, selective modulation of S1PR’s activity on human BMSCs may provide an effective approach to immunotherapy or tissue regeneration. Yaxian Kong, Hong Wang, Tao Lin, and Shuling Wang Copyright © 2014 Yaxian Kong et al. All rights reserved. Red Ginseng Extract Ameliorates Autoimmune Arthritis via Regulation of STAT3 Pathway, Th17/Treg Balance, and Osteoclastogenesis in Mice and Human Wed, 23 Jul 2014 11:46:03 +0000 Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation. Red ginseng is a steamed and dried Panax ginseng C.A. Meyer, which has been used as alternative medicine for thousands of years. This study was undertaken to investigate the effects of red ginseng extracts (RGE) on autoimmune arthritis in mice and humans and to delineate the underlying mechanism. RGE was orally administered three times a week to mice with arthritis. Oral administration of RGE markedly ameliorated clinical arthritis score and histologically assessed joint inflammation in mice with CIA. A significant reduction in STAT3 phosphorylation and a decrease in the number of Th17 cells were observed with RGE treatment. There was also a marked reduction in RANKL-induced osteoclastogenesis with treatment of RGE. The inhibitory effect of RGE on Th17 differentiation and osteoclastogenesis observed in mice was also confirmed in the subsequent experiments performed using human peripheral blood mononuclear cells. Our findings provide the first evidence that RGE can regulate Th17 and reciprocally promote Treg cells by inhibiting the phosphorylation of STAT3. Therefore, RGE can ameliorate arthritis in mice with CIA by targeting pathogenic Th17 and osteoclast differentiation, suggesting a novel therapy for treatment of RA. JooYeon Jhun, Jennifer Lee, Jae-Kyeong Byun, Eun-Kyung Kim, Jung-Won Woo, Jae-Ho Lee, Seung-Ki Kwok, Ji-Hyeon Ju, Kyung-Su Park, Ho-Youn Kim, Sung Hwan Park, and Mi-La Cho Copyright © 2014 JooYeon Jhun et al. 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.