Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Cytokine and Growth Factor Activation In Vivo and In Vitro after Spinal Cord Injury Thu, 23 Jun 2016 07:43:56 +0000 Spinal cord injury results in a life-disrupting series of deleterious interconnected mechanisms encompassed by the primary and secondary injury. These events are mediated by the upregulation of genes with roles in inflammation, transcription, and signaling proteins. In particular, cytokines and growth factors are signaling proteins that have important roles in the pathophysiology of SCI. The balance between the proinflammatory and anti-inflammatory effects of these molecules plays a critical role in the progression and outcome of the lesion. The excessive inflammatory Th1 and Th17 phenotypes observed after SCI tilt the scale towards a proinflammatory environment, which exacerbates the deleterious mechanisms present after the injury. These mechanisms include the disruption of the spinal cord blood barrier, edema and ion imbalance, in particular intracellular calcium and sodium concentrations, glutamate excitotoxicity, free radicals, and the inflammatory response contributing to the neurodegenerative process which is characterized by demyelination and apoptosis of neuronal tissue. Elisa Garcia, Jorge Aguilar-Cevallos, Raul Silva-Garcia, and Antonio Ibarra Copyright © 2016 Elisa Garcia et al. All rights reserved. Reduced Parasite Burden in Children with Falciparum Malaria and Bacteremia Coinfections: Role of Mediators of Inflammation Wed, 22 Jun 2016 14:35:32 +0000 Bacteremia and malaria coinfection is a common and life-threatening condition in children residing in sub-Saharan Africa. We previously showed that coinfection with Gram negative (G[−]) enteric Bacilli and Plasmodium falciparum (Pf[+]) was associated with reduced high-density parasitemia (HDP, >10,000 parasites/μL), enhanced respiratory distress, and severe anemia. Since inflammatory mediators are largely unexplored in such coinfections, circulating cytokines were determined in four groups of children (, aged <3 yrs): healthy; Pf[+] alone; G[−] coinfected; and G[+] coinfected. Staphylococcus aureus and non-Typhi Salmonella were the most frequently isolated G[+] and G[−] organisms, respectively. Coinfected children, particularly those with G[−] pathogens, had lower parasite burden (peripheral and geometric mean parasitemia and HDP). In addition, both coinfected groups had increased IL-4, IL-5, IL-7, IL-12, IL-15, IL-17, IFN-γ, and IFN-α and decreased TNF-α relative to malaria alone. Children with G[−] coinfection had higher IL-1β and IL-1Ra and lower IL-10 than the Pf[+] group and higher IFN-γ than the G[+] group. To determine how the immune response to malaria regulates parasitemia, cytokine production was investigated with a multiple mediation model. Cytokines with the greatest mediational impact on parasitemia were IL-4, IL-10, IL-12, and IFN-γ. Results here suggest that enhanced immune activation, especially in G[−] coinfected children, acts to reduce malaria parasite burden. Gregory C. Davenport, James B. Hittner, Vincent Otieno, Zachary Karim, Harshini Mukundan, Paul W. Fenimore, Nicolas W. Hengartner, Benjamin H. McMahon, Prakasha Kempaiah, John M. Ong’echa, and Douglas J. Perkins Copyright © 2016 Gregory C. Davenport et al. All rights reserved. Effect of Toll-Like Receptor 4 on Synovial Injury of Temporomandibular Joint in Rats Caused by Occlusal Interference Mon, 20 Jun 2016 10:44:08 +0000 Synovitis is an important disease that causes intractable pain in TMJ. Some investigations suggested that the increasing expression of IL-1β secreted by synovial lining cells plays an important role in synovial inflammation and cartilage destruction in TMJ. In our previous research, the results demonstrated that TLR4 is involved in the expression of IL-1β in SFs from TMJ with lipopolysaccharide stimulation. However, the inflammatory response that occurred in synovial membrane is not caused by bacterial infection. In the current study, we investigated whether or not TLR4 participates in the inflammatory responses and the expression of IL-1β in synovial membrane of rats induced by occlusal interference. The results showed that obvious inflammation changes were observed in the synovial membranes and the expression of TLR4 and IL-1β was increased at both mRNA and protein levels in the occlusal interference rats. In addition, the inflammation reactions and the increased expression of IL-1β could be restrained by treatment with TAK-242, a blocker of TLR4 signaling. The results prompted us that the activation of TLR4 may be involved in the inflammatory reactions and increased expression of IL-1β in patients with synovitis and participate in the mechanisms of the initiation and development of synovial injury by regulating the expression of inflammatory mediators like IL-1β in synovial membranes. Jingjing Kong, Yingying Yang, Shuzhen Sun, Jianli Xie, Xuefen Lin, and Ping Ji Copyright © 2016 Jingjing Kong et al. All rights reserved. Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders Mon, 20 Jun 2016 09:31:51 +0000 Insulin resistance and other risk factors for atherosclerosis, such as hypertension and hypercholesterolemia, promote endothelial dysfunction and lead to development of metabolic syndrome which constitutes an introduction to cardiovascular disease. The insulin resistance and endothelial dysfunction cross talk between each other by numerous metabolic pathways. Hence, targeting one of these pathologies with pleiotropic treatment exerts beneficial effect on another one. Combined and expletive treatment of hypertension, lipid disorders, and insulin resistance with nonpharmacological interventions and conventional pharmacotherapy may inhibit the transformation of metabolic disturbances to fully developed cardiovascular disease. This paper summarises the common therapeutic targets for insulin resistance, endothelial dysfunction, and vascular inflammatory reaction at molecular level and analyses the potential pleiotropic effects of drugs used currently in management of cardiovascular disease, metabolic syndrome, and diabetes. A. Janus, E. Szahidewicz-Krupska, G. Mazur, and A. Doroszko Copyright © 2016 A. Janus et al. All rights reserved. PGC-1α-Dependent Mitochondrial Adaptation Is Necessary to Sustain IL-2-Induced Activities in Human NK Cells Mon, 20 Jun 2016 06:39:36 +0000 Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in antitumor defense reactions. NK cell effector functions are critically dependent on cytokines and metabolic activity. Among various cytokines modulating NK cell function, interleukin-2 (IL-2) can induce a more potent cytotoxic activity defined as lymphokine activated killer activity (LAK). Our aim was to determine if IL-2 induces changes at the mitochondrial level in NK cells to support the bioenergetic demand for performing this enhanced cytotoxic activity more efficiently. Purified human NK cells were cultured with high IL-2 concentrations to develop LAK activity, which was assessed by the ability of NK cells to lyse NK-resistant Daudi cells. Here we show that, after 72 h of culture of purified human NK cells with enough IL-2 to induce LAK activity, both the mitochondrial mass and the mitochondrial membrane potential increased in a PGC-1α-dependent manner. In addition, oligomycin, an inhibitor of ATP synthase, inhibited IL-2-induced LAK activity at 48 and 72 h of culture. Moreover, the secretion of IFN-γ from NK cells with LAK activity was also partially dependent on PGC-1α expression. These results indicate that PGC-1α plays a crucial role in regulating mitochondrial function involved in the maintenance of LAK activity in human NK cells stimulated with IL-2. Dante Miranda, Claudia Jara, Jorge Ibañez, Viviana Ahumada, Claudio Acuña-Castillo, Adrian Martin, Alexandra Córdova, and Margarita Montoya Copyright © 2016 Dante Miranda et al. All rights reserved. The Early Expression of HLA-DR and CD64 Myeloid Markers Is Specifically Compartmentalized in the Blood and Lungs of Patients with Septic Shock Sun, 19 Jun 2016 11:08:21 +0000 Identification of reliable biomarkers is key to guide targeted therapies in septic patients. Expression monitoring of monocyte HLA-DR and neutrophil CD64 could fulfill the above need. However, it is unknown whether their expression on circulating cells reflects the status of tissue resident cells. We compared expressions of HLA-DR and CD64 markers in the circulation and airways of septic shock patients and evaluated their outcome prognostic value. The expression of CD64 on neutrophils and HLA-DR on monocytes was analyzed in the peripheral blood and mini-bronchoalveolar lavage fluid cells by flow cytometry. Twenty-seven patients with septic shock were enrolled into the study. The fluorescence intensity of HLA-DR on circulating monocytes was 3.5-fold lower than on the pulmonary monocytes (). The expression of CD64 on circulating and airway neutrophils was similar (). Only the expression of CD64 on circulating neutrophils was higher in nonsurvivors versus survivors (2.8-fold; ). Pulmonary monocytes display a higher level of HLA-DR activation compared to peripheral blood monocytes but the expression of neutrophil CD64 is similar on lung and circulating cells. Death in septic patients was effectively predicted by neutrophil CD64 but not monocytic HLA-DR. Prognostic value of cellular activation markers in septic shock appears to strongly depend on their level of compartmentalization. Tomasz Skirecki, Małgorzata Mikaszewska-Sokolewicz, Grażyna Hoser, and Urszula Zielińska-Borkowska Copyright © 2016 Tomasz Skirecki et al. All rights reserved. Balancing Inflammation: The Link between Th17 and Regulatory T Cells Sun, 19 Jun 2016 09:04:33 +0000 CD4+ T cell compartments in mouse and man are composed of multiple distinct subsets each possessing unique phenotypic and functional characteristics. IL-17-producing CD4+ T cells (Th17 cells) represent a distinct subset of the CD4+ T cell lineage. Recent evidence suggests that Th17 cells carry out effector functions similar to cytotoxic CD8+ T cells and play an important role in the clearance of extracellular pathogens and fungi. Th17 cell differentiation and function are closely related to the development and function of regulatory T cells . The balance between these two cell populations is essential for immune homeostasis and dysregulation of this balance has been implicated in a variety of inflammatory conditions including autoimmunity, allograft rejection, and tumorigenesis. Emerging evidence reports a significant amount of plasticity between the Th17 and regulatory T cell compartments, and the mechanisms by which these cells communicate and influence each other are just beginning to be understood. In this review, we highlight recent findings detailing the mechanisms driving Th17 and plasticity and discuss the biologic consequences of their unique relationship. Maggie L. Diller, Ragini R. Kudchadkar, Keith A. Delman, David H. Lawson, and Mandy L. Ford Copyright © 2016 Maggie L. Diller et al. All rights reserved. Triptolide Inhibits Osteoclast Differentiation and Bone Resorption In Vitro via Enhancing the Production of IL-10 and TGF-β1 by Regulatory T Cells Sun, 19 Jun 2016 08:23:22 +0000 Triptolide, a purified component of Tripterygiumwilfordii Hook F, has been shown to have immunosuppressive and anti-inflammatory properties in rheumatoid arthritis (RA). Although triptolide has demonstrated that it could suppress bone destruction in collagen-induced mice, its therapeutic mechanism remains unclear. Many studies have investigated the effect of triptolide on Tregs and Tregs-related cytokine involved in RA. Additionally, previous studies have implied that Tregs inhibit osteoclast differentiation and bone resorption. Thus, in this study we aimed to explore the regulatory mechanism by which triptolide influences the Treg-mediated production of IL-10 and TGF-β1 to affect osteoclast differentiation and bone resorption. In cocultures system of Tregs and mouse bone marrow macrophages (BMMs), Tregs inhibited the differentiation of osteoclasts and reduced the resorbed areas significantly and the production of both IL-10 and TGF-β1 was upregulated. When the coculture systems were pretreated with triptolide, they produced higher levels of IL-10 and TGF-β1. Our data indicate that triptolide enhances the suppressive effects of Tregs on osteoclast differentiation and bone resorption by enhancing the secretion of IL-10 and TGF-β1. Tregs are most likely involved in the triptolide-mediated regulation of bone metabolism and may provide a potential therapeutic target for the treatment of inflammatory bone destruction. Huihui Xu, Hongyan Zhao, Cheng Lu, Qi Qiu, Gui Wang, Jing Huang, Minghui Guo, Baosheng Guo, Yong Tan, and Cheng Xiao Copyright © 2016 Huihui Xu et al. All rights reserved. Diagnostic Accuracy of Five Different Fecal Markers for the Detection of Precancerous and Cancerous Lesions of the Colorectum Thu, 16 Jun 2016 14:38:00 +0000 Background. Colorectal cancer (CRC) is the second deadliest malignancy worldwide. This study aimed to compare the diagnostic accuracy of different fecal markers in the detection of colorectal adenomas and cancer. Methods. Stool samples of patients referred to colonoscopy were collected for the analysis of tumor M2 pyruvate kinase (M2PK), human hemoglobin (Hb), hemoglobin/haptoglobin (Hb/Hp) complex, fecal calprotectin (FC), and matrix metalloproteinase-9 (MMP-9). Results. Sensitivity and specificity of M2PK for adenomas sized > 1 cm were 60% and 67.5% and for CRC were 94.7% and 67.5%. Sensitivity and specificity of iFOBT for adenomas sized ≥ 1 cm were 80% and 72.5% and for CRC were 94.7% and 72.5%. Sensitivity and specificity of Hb/Hp complex for adenomas sized ≥ 1 cm were 80% and 52.9% and for CRC were 100% and 52.9%. Sensitivity of FC and MMP-9 for CRC was 77.8% and 72.2%. Combined use of M2PK, iFOBT, and FC resulted in a sensitivity and specificity of 95% and 47.5% for the detection of adenomas sized ≥ 1 cm. Discussion. In CRC, sensitivity of M2PK, iFOBT, and Hb/Hp complex proved to be high. Combined use of M2PK, iFOBT, and FC may be valuable in the detection of large adenomas. Mariann Rutka, Renáta Bor, Anita Bálint, Anna Fábián, Ágnes Milassin, Ferenc Nagy, Zoltán Szepes, Mónika Szűcs, László Tiszlavicz, Klaudia Farkas, and Tamás Molnár Copyright © 2016 Mariann Rutka et al. All rights reserved. Expression Profile of Cationic Amino Acid Transporters in Rats with Endotoxin-Induced Uveitis Thu, 16 Jun 2016 14:24:35 +0000 Purpose. The transcellular arginine transportation via cationic amino acid transporter (CAT) is the rate-limiting step in nitric oxide (NO) synthesis, which is crucial in intraocular inflammation. In this study, CAT isoforms and inducible nitric oxide synthase (iNOS) expression was investigated in endotoxin-induced uveitis (EIU). Methods. EIU was induced in Lewis rats by lipopolysaccharide (LPS) injection. In the treatment group, the rats were injected intraperitoneally with the proteasome inhibitor bortezomib before EIU induction. After 24 hours, leukocyte quantification, NO measurement of the aqueous humor, and histopathological examination were evaluated. The expression of CAT isoforms and iNOS was determined by reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence staining. Nuclear factor-kappa B (NF-κB) binding activity was evaluated by electrophoretic mobility shift assay. The mouse macrophage cell line RAW 264.7 was used to validate the in vivo findings. Results. LPS significantly stimulated iNOS, CAT-2A, and CAT-2B mRNA and protein expression but did not affect CAT-1 in EIU rats and RAW 264.7 cells. Bortezomib attenuated inflammation and inhibited iNOS, CAT-2A, and CAT-2B expression through NF-κB inhibition. Conclusions. CAT-2 and iNOS, but not CAT-1, are specifically involved in EIU. NF-κB is essential in the induction of CAT-2 and iNOS in EIU. Yung-Ray Hsu, Shu-Wen Chang, Chang-Hao Yang, Yi-An Lee, and Tzu-Yun Kao Copyright © 2016 Yung-Ray Hsu et al. All rights reserved. Infusion of Hibiscus sabdariffa L. Modulates Oxidative Stress in Patients with Marfan Syndrome Thu, 16 Jun 2016 11:27:08 +0000 Marfan syndrome (MFS) is associated with progressive aortic dilatation, endothelial dysfunction, and oxidative stress that contribute to the early acute dissection of the vessel and can end up in rupture of the aorta and sudden death. Many studies have described that the organic acids from Hibiscus sabdariffa Linne (HSL) calyces increase cellular antioxidant capacity and decrease oxidative stress. Here we evaluate if the antioxidant properties of HSL infusion improve oxidative stress in MFS patients. Activities of extra cellular super oxide dismutase (ECSOD), glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GSSG-R), glutathione (GSH), lipid peroxidation (LPO) index, total antioxidant capacity (TAC), and ascorbic acid were determined in plasma from MFS patients. Values before and after 3 months of the treatment with 2% HSL infusion were compared in control and MFS subjects. After treatment, there was a significant decrease in ECSOD (), EGPx (), GST (), GSH (), and TAC and ascorbic acid () but GSSG-R activity () and LPO () were increased in MFS patients in comparison to patients receiving the HSL treatment and C subjects. Therefore, the infusion of HSL calyces has antioxidant properties that allow an increase in antioxidant capacity of both the enzymatic and nonenzymatic systems, in the plasma of the MSF patients. María Elena Soto, Alejandra Zuñiga-Muñoz, Verónica Guarner Lans, Erendira Janet Duran-Hernández, and Israel Pérez-Torres Copyright © 2016 María Elena Soto et al. All rights reserved. Krüppel-Like Factor 4 Is a Regulator of Proinflammatory Signaling in Fibroblast-Like Synoviocytes through Increased IL-6 Expression Thu, 16 Jun 2016 08:14:42 +0000 Human fibroblast-like synoviocytes play a vital role in joint synovial inflammation in rheumatoid arthritis (RA). Proinflammatory cytokines induce fibroblast-like synoviocyte activation and dysfunction. The inflammatory mediator Krüppel-like factor 4 is upregulated during inflammation and plays an important role in endothelial and macrophage activation during inflammation. However, the role of Krüppel-like factor 4 in fibroblast-like synoviocyte activation and RA inflammation remains to be defined. In this study, we identify the notion that Krüppel-like factor 4 is higher expressed in synovial tissues and fibroblast-like synoviocytes from RA patients than those from osteoarthritis patients. In vitro, the expression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes is induced by proinflammatory cytokine tumor necrosis factor-α. Overexpression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes robustly induced interleukin-6 production in the presence or absence of tumor necrosis factor-α. Conversely, knockdown of Krüppel-like factor 4 markedly attenuated interleukin-6 production in the presence or absence of tumor necrosis factor-α. Krüppel-like factor 4 not only can bind to and activate the interleukin-6 promoter, but also may interact directly with nuclear factor-kappa B. These results suggest that Krüppel-like factor 4 may act as a transcription factor mediating the activation of fibroblast-like synoviocytes in RA by inducing interleukin-6 expression in response to tumor necrosis factor-α. Xinjing Luo, Jie Chen, Jianwei Ruan, Yongfeng Chen, Xuanrong Mo, Jiangwen Xie, and Guoju Lv Copyright © 2016 Xinjing Luo et al. All rights reserved. Role of Porphyromonas gingivalis HmuY in Immunopathogenesis of Chronic Periodontitis Wed, 15 Jun 2016 09:30:04 +0000 Periodontitis is a multifactorial disease, with participation of bacterial, environmental, and host factors. It results from synergistic and dysbiotic multispecies microorganisms, critical “keystone pathogens,” affecting the whole bacterial community. The purpose of this study was to review the role of Porphyromonas gingivalis in the immunopathogenesis of chronic periodontitis, with special attention paid to HmuY. The host response during periodontitis involves the innate and adaptive immune system, leading to chronic inflammation and progressive destruction of tooth-supporting tissues. In this proinflammatory process, the ability of P. gingivalis to evade the host immune response and access nutrients in the microenvironment is directly related to its survival, proliferation, and infection. Furthermore, heme is an essential nutrient for development of these bacteria, and HmuY is responsible for its capture from host heme-binding proteins. The inflammatory potential of P. gingivalis HmuY has been shown, including induction of high levels of proinflammatory cytokines and CCL2, decreased levels of IL-8, and increased levels of anti-HmuY IgG and IgG1 antibodies in individuals with chronic periodontitis. Therefore, the HmuY protein might be a promising target for therapeutic strategies and for development of diagnostic methods in chronic periodontitis, especially in the case of patients with chronic periodontitis not responding to treatment, monitoring, and maintenance therapy. P. C. Carvalho-Filho, I. S. Gomes-Filho, R. Meyer, T. Olczak, M. T. Xavier, and S. C. Trindade Copyright © 2016 P. C. Carvalho-Filho et al. All rights reserved. Regulator of Calcineurin 1 in Periodontal Disease Wed, 15 Jun 2016 07:39:33 +0000 Nuclear factor of activated T-cells (NFAT) and NF-kB pathway associated processes are involved in the pathogenesis of various inflammatory disorders, for example, periodontal disease. The activation of these pathways is controlled by the regulator of calcineurin 1 (RCAN1). The aim of this study was to elucidate the role of RCAN1 in periodontal disease. Healthy and inflamed periodontal tissues were analyzed by immunohistochemistry and immunofluorescence using specific rabbit polyclonal anti-RCAN1 antibodies. For expression analysis human umbilical vein endothelial cells (HUVEC) were used. HUVEC were incubated for 2 h with Vascular Endothelial Growth Factor (VEGF) or with wild type and laboratory strains of Porphyromonas gingivalis (P. gingivalis). Expression analysis of rcan1 and cox2 was done by real time PCR using specific primers for rcan1.4 and cox2. The expression of rcan1 was found to be significantly suppressed in endothelial cells of chronically inflamed periodontal tissues compared to healthy controls. Rcan1 and cox2 were significantly induced by VEGF and wild type and laboratory P. gingivalis strains. Interestingly, the magnitude of the rcan1 and cox2 induction was strain dependent. The results of this study indicate that RCAN1 is suppressed in endothelial cells of chronically inflamed periodontal tissues. During an acute infection, however, rcan1 seems to be upregulated in endothelial cells, indicating a modulating role in immune homeostasis of periodontal tissues. Ulrike Peters, Eleni Solominidou, Yüksel Korkmaz, Stefan Rüttermann, Astrid Klocke, Thomas Frank Flemmig, and Thomas Beikler Copyright © 2016 Ulrike Peters et al. All rights reserved. Interleukin-27 as a Novel Biomarker for Early Cardiopulmonary Failure in Enterovirus 71-Infected Children with Central Nervous System Involvement Wed, 15 Jun 2016 06:23:38 +0000 Enterovirus 71 (EV71) is a major pathogen for severe hand, foot, and mouth disease (HFMD), which leads to severe neurological complications and has high morbidity and mortality. Reliable biomarker for the prediction of deterioration in EV71-infected children with central nervous system (CNS) involvement may reduce the cardiopulmonary failure and mortality. Here, we found that serum IL-27 levels were significantly higher in stage III EV71-infected HFMD patients with early cardiopulmonary failure and strong correlation with CRP levels. IL27p28 polymorphisms (rs153109, rs17855750, and rs181206) did not influence IL-27 production, and these three SNPs were not associated with EV71 infection risk and clinical stage. IL-27 can be used as an prediction indicator for early cardiopulmonary failure in EV71-infected children with CNS involvement. Mingyuan Huang, Wenjing Du, Jun Liu, Haiyang Zhang, Longbin Cao, Weiqing Yang, Hui Zhang, Zhiyong Wang, Pei Wei, Weiquan Wu, Zhulin Huang, Ying Fang, Qiling Lin, Xingwen Qin, Zhizhong Zhang, Keyuan Zhou, and Jincheng Zeng Copyright © 2016 Mingyuan Huang et al. All rights reserved. Metallothioneins 1 and 2 Modulate Inflammation and Support Remodeling in Ischemic Cardiomyopathy in Mice Tue, 14 Jun 2016 10:42:27 +0000 Aims. Repetitive brief ischemia and reperfusion () is associated with left ventricular dysfunction during development of ischemic cardiomyopathy. We investigated the role of zinc-donor proteins metallothionein MT1 and MT2 in a closed-chest murine model of . Methods. Daily 15-minute LAD-occlusion was performed for 1, 3, and 7 days in SV129 (WT)- and MT1/2 knockout (M)-mice ( = 8–10/group). Hearts were examined with M-mode echocardiography and processed for histological and mRNA studies. Results. Expression of MT1/2 mRNA was transiently induced during repetitive in WT-mice, accompanied by a transient inflammation, leading to interstitial fibrosis with left ventricular dysfunction without infarction. In contrast, M-hearts presented with enhanced apoptosis and small infarctions leading to impaired global and regional pump function. Molecular analysis revealed maladaptation of myosin heavy chain isoforms and antioxidative enzymes in MT1/-hearts. Despite their postponed chemokine induction we found a higher total neutrophil density and macrophage infiltration in small infarctions in M-hearts. Subsequently, higher expression of osteopontin 1 and tenascin C was associated with increased myofibroblast density resulting in predominately nonreversible fibrosis and adverse remodeling in MT1/-hearts. Conclusion. Cardioprotective effects of MT1/2 seem to be exerted via modulation of contractile elements, antioxidative enzymes, inflammatory response, and myocardial remodeling. Georg D. Duerr, Daniela Dewald, Eva J. Schmitz, Luise Verfuerth, Katharina Keppel, Christine Peigney, Alexander Ghanem, Armin Welz, and Oliver Dewald Copyright © 2016 Georg D. Duerr et al. All rights reserved. NF-κB-Regulated miR-99a Modulates Endothelial Cell Inflammation Tue, 14 Jun 2016 09:31:17 +0000 Objective. The present study was performed to investigate the effects and mechanisms of miR-99a on LPS-induced endothelial cell inflammation, as well as the regulation of NF-κB on miR-99a production. Methods and Results. ELISA showed that LPS treatment significantly promoted the secretion of inflammatory factors (TNF-α, IL-6, IL-1β, and MCP-1). LPS treatment also inhibited miR-99a production and promoted mTOR expression and NF-κB nuclear translocation. Overexpression of miR-99a suppressed the LPS-induced TNF-α, IL-6, IL-1β, and MCP-1 overproduction, mTOR upregulation, and NF-κB nuclear translocation. The PROMO software analysis indicated NF-κB binding site in the −1643 to −1652 region of miR-99a promoter. Dual luciferase reporter analysis, electrophoretic mobility shift assays (EMSA), and chromosome immunoprecipitation (ChIP) assays demonstrated that NF-κB promoted the transcription of miR-99a by binding to the −1643 to −1652 region of miR-99a promoter. Further studies on HUVECs verified the regulatory effects of NF-κB on miR-99a production. Conclusion. MiR-99a inhibited the LPS-induced HUVECs inflammation via inhibition of the mTOR/NF-κB signal. NF-κB promoted miR-99a production by binding to the −1643 to −1652 region of miR-99a promoter. Considering the importance of endothelial inflammation on cardiovascular diseases, such as atherosclerosis, our results may provide a new insight into the pathogenesis and therapy of atherosclerosis. Mei-hua Bao, Jian-Ming Li, Huai-qing Luo, Liang Tang, Qiao-li Lv, Guang-yi Li, and Hong-hao Zhou Copyright © 2016 Mei-hua Bao et al. All rights reserved. Adrenal-Derived Hormones Differentially Modulate Intestinal Immunity in Experimental Colitis Tue, 14 Jun 2016 06:48:44 +0000 The adrenal glands are able to modulate immune responses through neuroimmunoendocrine interactions and cortisol secretion that could suppress exacerbated inflammation such as in inflammatory bowel disease (IBD). Therefore, here we evaluated the role of these glands in experimental colitis induced by 3% dextran sulfate sodium (DSS) in C57BL/6 mice subjected to adrenalectomy, with or without glucocorticoid (GC) replacement. Mice succumbed to colitis without adrenals with a higher clinical score and augmented systemic levels of IL-6 and lower LPS. Furthermore, adrenalectomy negatively modulated systemic regulatory markers. The absence of adrenals resulted in augmented tolerogenic lamina propria dendritic cells but no compensatory local production of corticosterone and decreased mucosal inflammation associated with increased IFN-γ and FasL in the intestine. To clarify the importance of GC in this scenario, GC replacement in adrenalectomized mice restored different markers to the same degree of that observed in DSS group. Finally, this is the first time that adrenal-derived hormones, especially GC, were associated with the differential local modulation of the gut infiltrate, also pointing to a relationship between adrenalectomy and the modulation of systemic regulatory markers. These findings may elucidate some neuroimmunoendocrine mechanisms that dictate colitis outcome. Patrícia Reis de Souza, Helioswilton Sales-Campos, Paulo José Basso, Viviani Nardini, Angelica Silva, Fernanda Banquieri, Vanessa Beatriz Freitas Alves, Javier Emílio Lazo Chica, Auro Nomizo, and Cristina Ribeiro de Barros Cardoso Copyright © 2016 Patrícia Reis de Souza et al. All rights reserved. Chemokines and Chemokine Receptors in the Development of Lupus Nephritis Tue, 14 Jun 2016 06:40:43 +0000 Lupus nephritis (LN) is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE), an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN. Xiaofeng Liao, Tharshikha Pirapakaran, and Xin M. Luo Copyright © 2016 Xiaofeng Liao et al. All rights reserved. C-Terminal Alpha-1 Antitrypsin Peptide: A New Sepsis Biomarker with Immunomodulatory Function Mon, 13 Jun 2016 11:44:43 +0000 Systemic inflammatory response syndrome (SIRS) is a life threatening condition and the leading cause of death in intensive care units. Although single aspects of pathophysiology have been described in detail, numerous unknown mediators contribute to the progression of this complex disease. The aim of this study was to elucidate the pathophysiological role of CAAP48, a C-terminal alpha-1 antitrypsin fragment, that we found to be elevated in septic patients and to apply this peptide as diagnostic marker for infectious and noninfectious etiologies of SIRS. Incubation of human polymorphonuclear neutrophils with synthetic CAAP48, the SNP-variant CAAP47, and several control peptides revealed intense neutrophil activation, induction of neutrophil chemotaxis, reduction of neutrophil viability, and release of cytokines. We determined the abundance of CAAP48 in patients with severe sepsis, severe SIRS of noninfectious origin, and viral infection. CAAP48 levels were 3-4-fold higher in patients with sepsis compared to SIRS of noninfectious origin and allowed discrimination of those patients with high sensitivity and specificity. Our results suggest that CAAP48 is a promising discriminatory sepsis biomarker with immunomodulatory functions, particularly on human neutrophils, supporting its important role in the host response and pathophysiology of sepsis. Nancy Blaurock, Diana Schmerler, Kerstin Hünniger, Oliver Kurzai, Katrin Ludewig, Michael Baier, Frank Martin Brunkhorst, Diana Imhof, and Michael Kiehntopf Copyright © 2016 Nancy Blaurock et al. All rights reserved. Semisynthesis of Derivatives of Oleanolic Acid from Syzygium aromaticum and Their Antinociceptive and Anti-Inflammatory Properties Mon, 13 Jun 2016 08:16:08 +0000 Oleanolic acid is a pentacyclic triterpenoid compound widely found in plants and well known for its medicinal properties. Oleanolic acid (OA) was isolated from the ethyl acetate extract of Syzygium aromaticum flower buds. Semisynthesis afforded both acetate and ester derivatives. The derived compounds were monitored with thin layer chromatography and confirmed with nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), Fourier infrared (FT-IR) spectroscopy, and melting point (Mp). All these compounds were evaluated for their analgesic and anti-inflammatory properties at a dose of 40 mg/kg. Significant analgesic and anti-inflammatory effects were noted for all OA-derived compounds. In the formalin-induced pain test, the derivatives showed better analgesic effects compared to their precursor, whereas, in the tale flick test, oleanolic acid proved to be superior in analgesic effects compared to all its derivatives with the exception of the acetyl derivative. Acute inflammatory tests showed that acetyl derivatives possessed better anti-inflammatory activity compared to the other compounds. In conclusion, semisynthesis of oleanolic acid yielded several derivatives with improved solubility and enhanced analgesic and anti-inflammatory properties. Sibusiso Rali, Opeoluwa O. Oyedeji, Olukayode O. Aremu, Adebola O. Oyedeji, and Benedicta N. Nkeh-Chungag Copyright © 2016 Sibusiso Rali et al. All rights reserved. MicroRNA-Regulated Proinflammatory Cytokines in Sarcopenia Mon, 13 Jun 2016 07:57:13 +0000 Sarcopenia has been defined as the aging-related disease with the declined mass, strength, and function of skeletal muscle, which is the major cause of frailty and falls in elders. The activation of inflammatory signal pathways due to diseases and aging is suggested to reveal the critical impact on sarcopenia. Several proinflammatory cytokines, especially interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), play crucial roles in modulation of inflammatory signaling pathway during the aging-related loss of skeletal muscle. MicroRNAs (miRNAs) have emerged as the important regulators for the mass and functional maintenance of skeletal muscle through regulating gene expression of proinflammatory cytokines. In this paper, we have systematically discussed regulatory mechanisms of miRNAs for the expression and secretion of inflammatory cytokines during sarcopenia, which will provide some novel targets and therapeutic strategies for controlling aging-related atrophy of skeletal muscle and corresponding chronic inflammatory diseases. Jingjing Fan, Xianjuan Kou, Yi Yang, and Ning Chen Copyright © 2016 Jingjing Fan et al. All rights reserved. Epithelial Anion Transport as Modulator of Chemokine Signaling Sun, 12 Jun 2016 07:43:44 +0000 The pivotal role of epithelial cells is to secrete and absorb ions and water in order to allow the formation of a luminal fluid compartment that is fundamental for the epithelial function as a barrier against environmental factors. Importantly, epithelial cells also take part in the innate immune system. As a first line of defense they detect pathogens and react by secreting and responding to chemokines and cytokines, thus aggravating immune responses or resolving inflammatory states. Loss of epithelial anion transport is well documented in a variety of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, pancreatitis, and cholestatic liver disease. Here we review the effect of aberrant anion secretion with focus on the release of inflammatory mediators by epithelial cells and discuss putative mechanisms linking these transport defects to the augmented epithelial release of chemokines and cytokines. These mechanisms may contribute to the excessive and persistent inflammation in many respiratory and gastrointestinal diseases. Andrea Schnúr, Péter Hegyi, Simon Rousseau, Gergely L. Lukacs, and Guido Veit Copyright © 2016 Andrea Schnúr et al. All rights reserved. Pretransplant Immune- and Apoptosis-Related Gene Expression Is Associated with Kidney Allograft Function Sun, 12 Jun 2016 07:11:44 +0000 Renal transplant candidates present immune dysregulation, caused by chronic uremia. The aim of the study was to investigate whether pretransplant peripheral blood gene expression of immune factors affects clinical outcome of renal allograft recipients. Methods. In a prospective study, we analyzed pretransplant peripheral blood gene expression in87 renal transplant candidates with real-time PCR on custom-designed low density arrays (TaqMan). Results. Immediate posttransplant graft function (14-day GFR) was influenced negatively by TGFB1 () and positively by IL-2 gene expression (). Pretransplant blood mRNA expression of apoptosis-related genes (CASP3, FAS, and IL-18) and Th1-derived cytokine gene IFNG correlated positively with short- (6-month GFR CASP3: , FAS: , and IFNG: ) and long-term graft function (24-month GFR CASP3: , FAS: , IL-18: , and IFNG: ). Conclusion. Lowered pretransplant Th1-derived cytokine and apoptosis-related gene expressions were a hallmark of subsequent worse kidney function but not of acute rejection rate. The pretransplant IFNG and CASP3 and FAS and IL-18 genes’ expression in the recipients’ peripheral blood is the possible candidate for novel biomarker of short- and long-term allograft function. Dorota Kamińska, Katarzyna Kościelska-Kasprzak, Paweł Chudoba, Oktawia Mazanowska, Mirosław Banasik, Marcelina Żabinska, Maria Boratyńska, Agnieszka Lepiesza, Agnieszka Gomółkiewicz, Piotr Dzięgiel, and Marian Klinger Copyright © 2016 Dorota Kamińska et al. All rights reserved. Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema Thu, 09 Jun 2016 11:30:16 +0000 Introduction. Acute exposure to high altitude induces inflammation. However, the relationship between inflammation and high altitude related illness such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS) is poorly understood. We tested if soluble urokinase-type plasminogen activator receptor (suPAR) plasma concentration, a prognostic factor for cardiovascular disease and marker for low grade activation of leukocytes, will predict susceptibility to HAPE and AMS. Methods. 41 healthy mountaineers were examined at sea level (SL, 446 m) and 24 h after rapid ascent to 4559 m (HA). 24/41 subjects had a history of HAPE and were thus considered HAPE-susceptible (HAPE-s). Out of the latter, 10/24 HAPE-s subjects were randomly chosen to suppress the inflammatory cascade with dexamethasone 8 mg bid 24 h prior to ascent. Results. Acute hypoxic exposure led to an acute inflammatory reaction represented by an increase in suPAR ( at SL versus at HA, ), CRP ( at SL versus at HA, ), and IL-6 ( at SL versus at HA, ) in all subjects except those receiving dexamethasone. The ascent associated decrease in PaO2 correlated with the increase in IL-6 (, ), but not suPAR (, ); the increase in IL-6 was not correlated with suPAR (, ). Baseline suPAR plasma concentration was higher in the HAPE-s group ( versus , ); no difference was found for CRP and IL-6 and for subjects developing AMS. Conclusion. High altitude exposure leads to an increase in suPAR plasma concentration, with the missing correlation between suPAR and IL-6 suggesting a cytokine independent, leukocyte mediated mechanism of low grade inflammation. The correlation between IL-6 and PaO2 suggests a direct effect of hypoxia, which is not the case for suPAR. However, suPAR plasma concentration measured before hypoxic exposure may predict HAPE susceptibility. Matthias Peter Hilty, Stefanie Zügel, Michele Schoeb, Katja Auinger, Christoph Dehnert, and Marco Maggiorini Copyright © 2016 Matthias Peter Hilty et al. All rights reserved. Effect of Traditional Chinese Medicine on Inflammatory Mediators in Pediatric Asthma Thu, 09 Jun 2016 11:05:27 +0000 Objective. To observe the effects of empirical prescriptions of traditional Chinese medicine (TCM) on inflammatory mediators in pediatric asthma and to explore the underlying molecular mechanism in the treatment of asthma. Methods. A total of 182 children with asthma were randomly placed into either the TCM group () or the salbutamol and montelukast (SM) group (). Patients in the TCM group were treated with a series of empirical prescriptions of TCM, while those in the SM group received salbutamol and montelukast. Both groups received their respective treatment for 12 weeks. There were 35 patients in TCM group and 34 patients in SM group providing venous blood. Real-time PCR was used to determine the mRNA expression levels of interleukin- (IL-) 10, IL-17, matrix metalloproteinase-9 (MMP-9), and transforming growth factor β1 (TGF-β1) in peripheral blood mononuclear cells before and after treatment. Enzyme-linked immunosorbent assay was used to measure the levels of IL-10, IL-17, MMP-9, and TGF-β1 in peripheral blood before and after treatment. Results. The mRNA expression of TGF-β1 in the SM group was downregulated () after treatment. No significant differences were found between the TCM group and the SM group after treatment (). In the TCM group, the levels of IL-10, IL-17, and MMP-9 significantly decreased after treatment (, 0.04, and 0.03, resp.). In the SM group, IL-17, MMP-9, and TGF-β1 levels significantly decreased after treatment (, 0.03, and 0.00, resp.). There was no significant difference between the two groups regarding the levels of IL-10, IL-17, TGF-β1, and MMP-9 (). The difference of the level of IL-17 was negatively correlated with the change of C-ACT score in TCM group and SM group. Conclusion. TCM has a regulatory effect on the balance of some inflammatory mediators in pediatric asthma. Hui Du, Yonghong Wang, Yumin Shi, Jian Yu, Wen Sun, and Yiqun Zhang Copyright © 2016 Hui Du et al. All rights reserved. Caspase-11 Modulates Inflammation and Attenuates Toxoplasma gondii Pathogenesis Thu, 09 Jun 2016 11:03:59 +0000 Toxoplasma gondii is an obligate intracellular parasite that is the etiologic agent responsible for toxoplasmosis. Infection with T. gondii results in activation of nucleotide binding domain and leucine rich repeat containing receptors (NLRs). NLR activation leads to inflammasome formation, the activation of caspase-1, and the subsequent cleavage of IL-1β and IL-18. Recently, a noncanonical inflammasome has been characterized which functions through caspase-11 and appears to augment many biological functions previously considered to be dependent upon the canonical inflammasome. To better elucidate the function of this noncanonical inflammasome in toxoplasmosis, we utilized Asc−/− and Casp11−/− mice and infected these animals with T. gondii. Our data indicates that caspase-11 modulates the innate immune response to T. gondii through a mechanism which is distinct from that currently described for the canonical inflammasome. Asc−/− mice demonstrated increased disease pathogenesis during the acute phase of T. gondii infection, whereas Casp11−/− mice demonstrated significantly attenuated disease pathogenesis and reduced inflammation. This attenuated host response was associated with reduced local and systemic cytokine production, including diminished IL-1β. During the chronic phase of infection, caspase-11 deficiency resulted in increased neuroinflammation and tissue cyst burden in the brain. Together, our data suggest that caspase-11 functions to protect the host by enhancing inflammation during the early phase of infection in an effort to minimize disease pathogenesis during later stages of toxoplasmosis. Sheryl L. Coutermarsh-Ott, John T. Doran, Caroline Campbell, Tere M. Williams, David S. Lindsay, and Irving C. Allen Copyright © 2016 Sheryl L. Coutermarsh-Ott et al. All rights reserved. Small Interfering RNA Targeted to ASPP2 Promotes Progression of Experimental Proliferative Vitreoretinopathy Thu, 09 Jun 2016 06:14:39 +0000 Background. Epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) is vital in proliferative vitreoretinopathy (PVR) development. Apoptosis-stimulating proteins of p53 (ASPP2) have recently been reported to participate in EMT. However, the role of ASPP2 in PVR pathogenesis has not been identified. Methods. Immunohistochemistry was used to investigate the expression of ASPP2 in epiretinal membranes of PVR patients. ARPE-19 cells were transfected with ASPP2-siRNA, followed with measurement of cell cytotoxicity, proliferation, and migration ability. EMT markers and related inflammatory and fibrosis cytokines were measured by western blot or flow cytometry. Additionally, PVR rat models were induced by intravitreal injection of ARPE-19 cells transfected with ASPP2-siRNA and evaluated accordingly. Results. Immunofluorescence analysis revealed less intense expression of ASPP2 in PVR membranes. ASPP2 knockdown facilitated the proliferation and migration of RPE cells and enhanced the expression of mesenchymal markers such as alpha smooth muscle actin, fibronectin, and ZEB1. Meanwhile, ASPP2-siRNA increased EMT-related and inflammatory cytokines, including TGF-, CTGF, VEGF, TNF-α, and interleukins. PVR severities were more pronounced in the rat models with ASPP2-siRNA treatment. Conclusions. ASPP2 knockdown promoted EMT of ARPE-19 cells in vitro and exacerbated the progression of experimental PVR in vivo, possibly via inflammatory and fibrosis cytokines. Xiao-Li Chen, Yu-Jing Bai, Qin-Rui Hu, Shan-Shan Li, Lv-Zhen Huang, and Xiao-Xin Li Copyright © 2016 Xiao-Li Chen et al. All rights reserved. Induction of Mast Cell Accumulation by Tryptase via a Protease Activated Receptor-2 and ICAM-1 Dependent Mechanism Thu, 09 Jun 2016 06:05:16 +0000 Mast cells are primary effector cells of allergy, and recruitment of mast cells in involved tissue is one of the key events in allergic inflammation. Tryptase is the most abundant secretory product of mast cells, but little is known of its influence on mast cell accumulation. Using mouse peritoneal model, cell migration assay, and flow cytometry analysis, we investigated role of tryptase in recruiting mast cells. The results showed that tryptase induced up to 6.7-fold increase in mast cell numbers in mouse peritoneum following injection. Inhibitors of tryptase, an antagonist of PAR-2 FSLLRY-NH2, and pretreatment of mice with anti-ICAM-1, anti-CD11a, and anti-CD18 antibodies dramatically diminished tryptase induced mast cell accumulation. On the other hand, PAR-2 agonist peptides SLIGRL-NH2 and tc-LIGRLO-NH2 provoked mast cell accumulation following injection. These implicate that tryptase induced mast cell accumulation is dependent on its enzymatic activity, activation of PAR-2, and interaction between ICAM-1 and LFA-1. Moreover, induction of trans-endothelium migration of mast cells in vitro indicates that tryptase acts as a chemoattractant. In conclusion, provocation of mast cell accumulation by mast cell tryptase suggests a novel self-amplification mechanism of mast cell accumulation. Mast cell stabilizers as well as PAR-2 antagonist agents may be useful for treatment of allergic reactions. Xin Liu, Junling Wang, Huiyun Zhang, Mengmeng Zhan, Hanqiu Chen, Zeman Fang, Chiyan Xu, Huifang Chen, and Shaoheng He Copyright © 2016 Xin Liu et al. All rights reserved. Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes Tue, 07 Jun 2016 08:41:11 +0000 C5a is an inflammatory mediator generated by complement activation that positively regulates various arms of immune defense, including Toll-like receptor 4 (TLR4) signaling. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is activated by pathogen products and cellular/tissue damage products and is a major contributor of IL-1β. In this study, we investigate whether C5a modulates lipopolysaccharide- (LPS-) induced NLRP3 inflammasome activation in myeloid cells. Appearance of plasma IL-1β during endotoxemia was reduced in mice when compared to wild-type mice. In vitro, C5a significantly enhanced LPS-induced production of IL-1β in bone marrow Ly6C-high inflammatory monocytes, accompanied by augmented intracellular pro-IL-1β expression. This effect was abolished during p38 blockade by SB 203580 and in the absence of C5aR1. Conversely, C5a suppressed LPS-induced macrophage production of IL-1β, which was accompanied by attenuated levels of pro-IL-1β, NLRP3, and caspase-1 expression. C5a’s suppressive effects were negated during phosphoinositide 3-kinase (PI3K) inhibition by wortmannin but were largely preserved in the absence of C5aR1. Thus, C5a bidirectionally amplifies TLR4-mediated NLRP3 inflammasome activation in monocytes while suppressing this pathway in macrophages. However, as C5aR1 deficiency attenuates the IL-1β response to LPS challenge in vivo, our results suggest overall that C5a augments physiologic inflammasome responses. Mikel D. Haggadone, Jamison J. Grailer, Fatemeh Fattahi, Firas S. Zetoune, and Peter A. Ward Copyright © 2016 Mikel D. Haggadone et al. All rights reserved.