Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Role of the Immunogenic and Tolerogenic Subsets of Dendritic Cells in Multiple Sclerosis Thu, 29 Jan 2015 14:27:22 +0000 Multiple sclerosis (MS) is an immune-mediated disorder in the central nervous system (CNS) characterized by inflammation and demyelination as well as axonal and neuronal degeneration. So far effective therapies to reverse the disease are still lacking; most therapeutic drugs can only ameliorate the symptoms or reduce the frequency of relapse. Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are key players in both mediating immune responses and inducing immune tolerance. Increasing evidence indicates that DCs contribute to the pathogenesis of MS and might provide an avenue for therapeutic intervention. Here, we summarize the immunogenic and tolerogenic roles of DCs in MS and review medicinal drugs that may affect functions of DCs and have been applied in clinic for MS treatment. We also describe potential therapeutic molecules that can target DCs by inducing anti-inflammatory cytokines and inhibiting proinflammatory cytokines in MS. Zhong-Xiang Xie, Hong-Liang Zhang, Xiu-Juan Wu, Jie Zhu, Di-Hui Ma, and Tao Jin Copyright © 2015 Zhong-Xiang Xie et al. All rights reserved. A Novel Minimal Invasive Mouse Model of Extracorporeal Circulation Thu, 29 Jan 2015 10:12:45 +0000 Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor α, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury. Shuhua Luo, Menglin Tang, Lei Du, Lina Gong, Jin Xu, Youwen Chen, Yabo Wang, Ke Lin, and Qi An Copyright © 2015 Shuhua Luo et al. All rights reserved. Transforming Growth Factor Beta Family: Insight into the Role of Growth Factors in Regulation of Fracture Healing Biology and Potential Clinical Applications Thu, 29 Jan 2015 06:34:04 +0000 The transforming growth factor beta (TGF-β) family forms a group of three isoforms, TGF-β1, TGF-β2, and TGF-β3, with their structure formed by interrelated dimeric polypeptide chains. Pleiotropic and redundant functions of the TGF-β family concern control of numerous aspects and effects of cell functions, including proliferation, differentiation, and migration, in all tissues of the human body. Amongst many cytokines and growth factors, the TGF-β family is considered a group playing one of numerous key roles in control of physiological phenomena concerning maintenance of metabolic homeostasis in the bone tissue. By breaking the continuity of bone tissue, a spread-over-time and complex bone healing process is initiated, considered a recapitulation of embryonic intracartilaginous ossification. This process is a cascade of local and systemic phenomena spread over time, involving whole cell lineages and various cytokines and growth factors. Numerous in vivo and in vitro studies in various models analysing cytokines and growth factors’ involvement have shown that TGF-β has a leading role in the fracture healing process. This paper sums up current knowledge on the basis of available literature concerning the role of the TGF-β family in the fracture healing process. Łukasz A. Poniatowski, Piotr Wojdasiewicz, Robert Gasik, and Dariusz Szukiewicz Copyright © 2015 Łukasz A. Poniatowski et al. All rights reserved. Anti-HMGB1 Monoclonal Antibody Ameliorates Immunosuppression after Peripheral Tissue Trauma: Attenuated T-Lymphocyte Response and Increased Splenic CD11b+Gr-1+ Myeloid-Derived Suppressor Cells Require HMGB1 Thu, 29 Jan 2015 06:33:38 +0000 Although tissue-derived high mobility group box 1 (HMGB1) is involved in many aspects of inflammation and tissue injury after trauma, its role in trauma-induced immune suppression remains elusive. Using an established mouse model of peripheral tissue trauma, which includes soft tissue and fracture components, we report here that treatment with anti-HMGB1 monoclonal antibody ameliorated the trauma-induced attenuated T-cell responses and accumulation of CD11b+Gr-1+ myeloid-derived suppressor cells in the spleens seen two days after injury. Our data suggest that HMGB1 released after tissue trauma contributes to signaling pathways that lead to attenuation of T-lymphocyte responses and enhancement of myeloid-derived suppressor cell expansion. Xiangcai Ruan, Sophie S. Darwiche, Changchun Cai, Melanie J. Scott, Hans-Christoph Pape, and Timothy R. Billiar Copyright © 2015 Xiangcai Ruan et al. All rights reserved. Local Inflammation in Fracture Hematoma: Results from a Combined Trauma Model in Pigs Wed, 28 Jan 2015 14:59:54 +0000 Background. Previous studies showed significant interaction between the local and systemic inflammatory response after severe trauma in small animal models. The purpose of this study was to establish a new combined trauma model in pigs to investigate fracture-associated local inflammation and gain information about the early inflammatory stages after polytrauma. Material and Methods. Combined trauma consisted of tibial fracture, lung contusion, liver laceration, and controlled hemorrhage. Animals were mechanically ventilated and under ICU-monitoring for 48 h. Blood and fracture hematoma samples were collected during the time course of the study. Local and systemic levels of serum cytokines and diverse alarmins were measured by ELISA kit. Results. A statistical significant difference in the systemic serum values of IL-6 and HMGB1 was observed when compared to the sham. Moreover, there was a statistical significant difference in the serum values of the fracture hematoma of IL-6, IL-8, IL-10, and HMGB1 when compared to the systemic inflammatory response. However a decrease of local proinflammatory concentrations was observed while anti-inflammatory mediators increased. Conclusion. Our data showed a time-dependent activation of the local and systemic inflammatory response. Indeed it is the first study focusing on the local and systemic inflammatory response to multiple-trauma in a large animal model. K. Horst, D. Eschbach, R. Pfeifer, S. Hübenthal, M. Sassen, T. Steinfeldt, H. Wulf, S. Ruchholtz, H. C. Pape, and F. Hildebrand Copyright © 2015 K. Horst et al. All rights reserved. Evaluation of Serum Amyloid A as a Marker of Persistent Inflammation in Patients with Rheumatoid Arthritis Wed, 28 Jan 2015 10:07:01 +0000 Mehmet Agilli, Fevzi Nuri Aydin, Tuncer Cayci, and Yasemin Gulcan Kurt Copyright © 2015 Mehmet Agilli et al. All rights reserved. NLRP3 Inflammasome: Activation and Regulation in Age-Related Macular Degeneration Wed, 28 Jan 2015 06:32:02 +0000 Age-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly in industrialized countries. AMD is a multifactorial disease influenced by both genetic and environmental risk factors. Progression of AMD is characterized by an increase in the number and size of drusen, extracellular deposits, which accumulate between the retinal pigment epithelium (RPE) and Bruch’s membrane (BM) in outer retina. The major pathways associated with its pathogenesis include oxidative stress and inflammation in the early stages of AMD. Little is known about the interactions among these mechanisms that drive the transition from early to late stages of AMD, such as geographic atrophy (GA) or choroidal neovascularization (CNV). As part of the innate immune system, inflammasome activation has been identified in RPE cells and proposed to be a causal factor for RPE dysfunction and degeneration. Here, we will first review the classic model of inflammasome activation, then discuss the potentials of AMD-related factors to activate the inflammasome in both nonocular immune cells and RPE cells, and finally introduce several novel mechanisms for regulating the inflammasome activity. Jiangyuan Gao, Ruozhou Tom Liu, Sijia Cao, Jing Z. Cui, Aikun Wang, Eleanor To, and Joanne A. Matsubara Copyright © 2015 Jiangyuan Gao et al. All rights reserved. Modulation of Extracellular ATP Content of Mast Cells and DRG Neurons by Irradiation: Studies on Underlying Mechanism of Low-Level-Laser Therapy Tue, 27 Jan 2015 07:47:33 +0000 Low-level-laser therapy (LLLT) is an effective complementary treatment, especially for anti-inflammation and wound healing in which dermis or mucus mast cells (MCs) are involved. In periphery, MCs crosstalk with neurons via purinergic signals and participate in various physiological and pathophysiological processes. Whether extracellular ATP, an important purine in purinergic signaling, of MCs and neurons could be modulated by irradiation remains unknown. In this study, effects of red-laser irradiation on extracellular ATP content of MCs and dorsal root ganglia (DRG) neurons were investigated and underlying mechanisms were explored in vitro. Our results show that irradiation led to elevation of extracellular ATP level in the human mast cell line HMC-1 in a dose-dependent manner, which was accompanied by elevation of intracellular ATP content, an indicator for ATP synthesis, together with [Ca2+]i elevation, a trigger signal for exocytotic ATP release. In contrast to MCs, irradiation attenuated the extracellular ATP content of neurons, which could be abolished by ARL 67156, a nonspecific ecto-ATPases inhibitor. Our results suggest that irradiation potentiates extracellular ATP of MCs by promoting ATP synthesis and release and attenuates extracellular ATP of neurons by upregulating ecto-ATPase activity. The opposite responses of these two cell types indicate complex mechanisms underlying LLLT. Lina Wang, Lei Hu, Ryszard Grygorczyk, Xueyong Shen, and Wolfgang Schwarz Copyright © 2015 Lina Wang et al. All rights reserved. Deficits in Endogenous Adenosine Formation by Ecto-5′-Nucleotidase/CD73 Impair Neuromuscular Transmission and Immune Competence in Experimental Autoimmune Myasthenia Gravis Tue, 27 Jan 2015 06:37:16 +0000 AMP dephosphorylation via ecto-5′-nucleotidase/CD73 is the rate limiting step to generate extracellular adenosine (ADO) from released adenine nucleotides. ADO, via receptors (Rs), is a potent modulator of neuromuscular and immunological responses. The pivotal role of ecto-5′-nucleotidase/CD73, in controlling extracellular ADO formation, prompted us to investigate its role in a rat model of experimental autoimmune myasthenia gravis (EAMG). Results show that CD4+CD25+FoxP3+ regulatory T cells express lower amounts of ecto-5′-nucleotidase/CD73 as compared to controls. Reduction of endogenous ADO formation might explain why proliferation of CD4+ T cells failed upon blocking receptors activation with ZM241385 or adenosine deaminase in EAMG animals. Deficits in ADO also contribute to neuromuscular transmission failure in EAMG rats. Rehabilitation of R-mediated immune suppression and facilitation of transmitter release were observed by incubating the cells with the nucleoside precursor, AMP. These findings, together with the characteristic increase in serum adenosine deaminase activity of MG patients, strengthen our hypothesis that the adenosinergic pathway may be dysfunctional in EAMG. Given that endogenous ADO formation is balanced by ecto-5′-nucleotidase/CD73 activity and that Rs exert a dual role to restore use-dependent neurocompetence and immune suppression in myasthenics, we hypothesize that stimulation of the two mechanisms may have therapeutic potential in MG. Laura Oliveira, Alexandra Correia, Ana Cristina Costa, Sónia Guerra-Gomes, Fátima Ferreirinha, Maria Teresa Magalhães-Cardoso, Manuel Vilanova, and Paulo Correia-de-Sá Copyright © 2015 Laura Oliveira et al. All rights reserved. Supplementation with Red Palm Oil Increases β-Carotene and Vitamin A Blood Levels in Patients with Cystic Fibrosis Mon, 26 Jan 2015 06:32:29 +0000 Patients with cystic fibrosis (CF) show decreased plasma concentrations of antioxidants due to malabsorption of lipid soluble vitamins and consumption by chronic pulmonary inflammation. β-Carotene is a major source of retinol and therefore is of particular significance in CF. The aim of this study was to investigate the effect of daily intake of red palm oil (RPO) containing high amounts of β-carotene on the antioxidant levels in CF patients. Sixteen subjects were recruited and instructed to enrich their food with 2 to 3 tablespoons of RPO (~1.5 mg of β-carotene) daily over 8 weeks. Carotenoids, retinol, and α-tocopherol were measured in plasma at baseline and after intervention. In addition β-carotene, lycopene, α-tocopherol, and vitamin C were measured in buccal mucosa cells (BMC) to determine the influence of RPO on antioxidant tissue levels. Eleven subjects completed the study properly. Plasma β-carotene, retinol, and α-carotene of these patients increased, but plasma concentrations of other carotenoids and α-tocopherol as well as concentrations of β-carotene, lycopene, α-tocopherol, and vitamin C in BMC remained unchanged. Since RPO on a daily basis did not show negative side effects the data suggest that RPO may be used to elevate plasma β-carotene in CF. Olaf Sommerburg, Silke De Spirt, Annett Mattern, Cornelia Joachim, Claus-Dieter Langhans, Kalanithi Nesaretnam, Werner Siems, Wilhelm Stahl, and Marcus A. Mall Copyright © 2015 Olaf Sommerburg et al. All rights reserved. Genetic Deletion of Soluble Epoxide Hydrolase Attenuates Inflammation and Fibrosis in Experimental Obstructive Nephropathy Thu, 22 Jan 2015 14:09:14 +0000 Soluble epoxide hydrolase (sEH) is abundantly expressed in kidney and plays a potent role in regulating inflammatory response in inflammatory diseases. However, the role of sEH in progression of chronic kidney diseases such as obstructive nephropathy is still elusive. In current study, wild-type (WT) and sEH deficient (sEH−/−) mice were subjected to the unilateral ureteral obstruction (UUO) surgery and the kidney injury was evaluated by histological examination, western blotting, and ELISA. The protein level of sEH in kidney was increased in UUO-treated mice group compared to nonobstructed group. Additionally, UUO-induced hydronephrosis, renal tubular injury, inflammation, and fibrosis were ameliorated in sEH−/− mice with the exception of glomerulosclerosis. Moreover, sEH−/− mice with UUO showed lower levels of inflammation-related and fibrosis-related protein such as monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase, collagen 1A1, and α-actin. The levels of superoxide anion radical and hydrogen peroxide as well as NADPH oxidase activity were also decreased in UUO kidneys of sEH−/− mice compared to that observed in WT mice. Collectively, our findings suggest that sEH plays an important role in the pathogenesis of experimental obstructive nephropathy and may be a therapeutic target for the treatment of obstructive nephropathy-related diseases. Chin-Wei Chiang, Hsueh-Te Lee, Der-Cherng Tarng, Ko-Lin Kuo, Li-Ching Cheng, and Tzong-Shyuan Lee Copyright © 2015 Chin-Wei Chiang et al. All rights reserved. Human Leucocyte Antigen-G (HLA-G) and Its Murine Functional Homolog Qa2 in the Trypanosoma cruzi Infection Tue, 20 Jan 2015 07:41:06 +0000 Genetic susceptibility factors, parasite strain, and an adequate modulation of the immune system seem to be crucial for disease progression after Trypanosoma cruzi infection. HLA-G and its murine functional homolog Qa2 have well-recognized immunomodulatory properties. We evaluated the HLA-G 3′ untranslated region (3′UTR) polymorphic sites (associated with mRNA stability and target for microRNA binding) and HLA-G tissue expression (heart, colon, and esophagus) in patients presenting Chagas disease, stratified according to the major clinical variants. Further, we investigated the transcriptional levels of Qa2 and other pro- and anti-inflammatory genes in affected mouse tissues during T. cruzi experimental acute and early chronic infection induced by the CL strain. Chagas disease patients exhibited differential HLA-G 3′UTR susceptibility allele/genotype/haplotype patterns, according to the major clinical variant (digestive/cardiac/mixed/indeterminate). HLA-G constitutive expression on cardiac muscle and colonic cells was decreased in Chagasic tissues; however, no difference was observed for Chagasic and non-Chagasic esophagus tissues. The transcriptional levels of Qa2 and other anti and proinflammatory (CTLA-4, PDCD1, IL-10, INF-γ, and NOS-2) genes were induced only during the acute T. cruzi infection in BALB/c and C57BL/6 mice. We present several lines of evidence indicating the role of immunomodulatory genes and molecules in human and experimental T. cruzi infection. Fabrício C. Dias, Celso T. Mendes-Junior, Maria C. Silva, Fabrine S. M. Tristão, Renata Dellalibera-Joviliano, Philippe Moreau, Edson G. Soares, Jean G. Menezes, André Schmidt, Roberto O. Dantas, José A. Marin-Neto, João S. Silva, and Eduardo A. Donadi Copyright © 2015 Fabrício C. Dias et al. All rights reserved. Prostacyclin Synthase: Upregulation during Renal Development and in Glomerular Disease as well as Its Constitutive Expression in Cultured Human Mesangial Cells Sun, 18 Jan 2015 12:17:16 +0000 Prostacyclin (PGI2) plays a critical role in nephrogenesis and renal physiology. However, our understanding of how prostacyclin release in the kidney is regulated remains poorly defined. We studied expression of prostacyclin synthase (PGIS) in developing and adult human kidneys, and also in selected pediatric renal diseases. We also examined PGI2 formation in human mesangial cells in vitro. We observed abundant expression of PGIS in the nephrogenic cortex in humans and in situ hybridization revealed an identical pattern in mice. In the normal adult kidney, PGIS-immunoreactive protein and mRNA appear to localize to mesangial fields and endothelial and smooth muscle cells of arteries and peritubular capillaries. In kidney biopsies taken from pediatric patients, enhanced expression of PGIS-immunoreactive protein was noted mainly in endothelial cells of patients with IgA-nephropathy. Cultured human mesangial cells produce primarily PGI2 and prostaglandin E2, followed by prostaglandin F2α Cytokine stimulation increased PGI2 formation 24-fold. Under these conditions expression of PGIS mRNA and protein remained unaltered whereas mRNA for cyclooxygenase-2 was markedly induced. In contrast to its constitutive expression in vitro, renal expression of prostacyclin-synthase appears to be regulated both during development and in glomerular disease. Further research is needed to identify the factors involved in regulation of PGIS-expression. Thomas Klein, Günther Klaus, and Martin Kömhoff Copyright © 2015 Thomas Klein et al. All rights reserved. Decreased Regulatory T Cells in Vulnerable Atherosclerotic Lesions: Imbalance between Pro- and Anti-Inflammatory Cells in Atherosclerosis Thu, 15 Jan 2015 14:06:59 +0000 Atherosclerosis is a chronic inflammatory disease of the arterial wall in which presentation of autoantigens by dendritic cells (DCs) leads to the activation of T cells. Anti-inflammatory cells like Tregs counterbalance inflammation in atherogenesis. In our study, human carotid plaque specimens were classified as stable (14) and unstable (15) according to established morphological criteria. Vessel specimens () without any signs of atherosclerosis were used as controls. Immunohistochemical staining was performed to detect different types of DCs (S100, fascin, CD83, CD209, CD304, and CD123), proinflammatory T cells (CD3, CD4, CD8, and CD161), and anti-inflammatory Tregs (FoxP3). The following results were observed: in unstable lesions, significantly higher numbers of proinflammatory cells like DCs, T helper cells, cytotoxic T cells, and natural killer cells were detected compared to stable plaques. Additionally, there was a significantly higher expression of HLA-DR and more T cell activation (CD25, CD69) in unstable lesions. On the contrary, unstable lesions contained significantly lower numbers of Tregs. Furthermore, a significant inverse correlation between myeloid DCs and Tregs was shown. These data suggest an increased inflammatory state in vulnerable plaques resulting from an imbalance of the frequency of local pro- and anti-inflammatory immune cells. Ilonka Rohm, Yevgeniya Atiskova, Stefanie Drobnik, Michael Fritzenwanger, Daniel Kretzschmar, Rudin Pistulli, Jürgen Zanow, Thomas Krönert, Gita Mall, Hans Reiner Figulla, and Atilla Yilmaz Copyright © 2015 Ilonka Rohm et al. All rights reserved. Protection from Endotoxic Uveitis by Intravitreal Resolvin D1: Involvement of Lymphocytes, miRNAs, Ubiquitin-Proteasome, and M1/M2 Macrophages Thu, 15 Jan 2015 10:10:05 +0000 This study investigated the protective effects of intravitreal Resolvin D1 (RvD1) against LPS-induced rat endotoxic uveitis (EIU). RvD1 was administered into the right eye at a single injection of 5 μL volume containing 10–100–1000 ng/kg RvD1 1 h post-LPS injection (200 μg, Salmonella minnesota) into thefootpad of Sprague-Dawley rats. 24 h later, the eye was enucleated and examined for clinical, biochemical, and immunohistochemical evaluations. RvD1 significantly and dose-dependently decreased the clinical score attributed to EIU, starting from the dose of 10 ng/kg and further decreased by 100 and 1000 ng/kg. These effects were accompanied by changes in four important determinants of the immune-inflammatory response within the eye: (i) the B and T lymphocytes, (ii) the miRNAs pattern, (iii) the ubiquitin-proteasome system (UPS), and (iv) the M1/M2 macrophage phenotype. LPS+RvD1 treated rats showed reduced presence of B and T lymphocytes and upregulation of miR-200c-3p, miR 203a-3p, miR 29b-3p, and miR 21-5p into the eye compared to the LPS alone. This was paralleled by decreases of the ubiquitin, 20S and 26S proteasome subunits, reduced presence of macrophage M1, and increased presence of macrophage M2 in the ocular tissues. Accordingly, the levels of the cytokine TNF-α, the chemokines MIP1-α and NF-κB were reduced. S. Rossi, C. Di Filippo, C. Gesualdo, N. Potenza, A. Russo, M. C. Trotta, M. V. Zippo, R. Maisto, F. Ferraraccio, F. Simonelli, and M. D’Amico Copyright © 2015 S. Rossi et al. All rights reserved. Cannabinoid Receptor CB2 Is Involved in Tetrahydrocannabinol-Induced Anti-Inflammation against Lipopolysaccharide in MG-63 Cells Wed, 14 Jan 2015 14:24:02 +0000 Cannabinoid Δ9-tetrahydrocannabinol (THC) is effective in treating osteoarthritis (OA), and the mechanism, however, is still elusive. Activation of cannabinoid receptor CB2 reduces inflammation; whether the activation CB2 is involved in THC-induced therapeutic action for OA is still unknown. Cofilin-1 is a cytoskeleton protein, participating in the inflammation of OA. In this study, MG-63 cells, an osteosarcoma cell-line, were exposed to lipopolysaccharide (LPS) to mimic the inflammation of OA. We hypothesized that the activation of CB2 is involved in THC-induced anti-inflammation in the MG-63 cells exposed to LPS, and the anti-inflammation is mediated by cofilin-1. We found that THC suppressed the release of proinflammatory factors, including tumor necrosis factor α (TNF-α), interleukin- (IL-) 1β, IL-6, and IL-8, decreased nuclear factor-κB (NF-κB) expression, and inhibited the upregulation of cofilin-1 protein in the LPS-stimulated MG-63 cells. However, administration of CB2 receptor antagonist or the CB2-siRNA, not CB1 antagonist AM251, partially abolished the THC-induced anti-inflammatory effects above. In addition, overexpression of cofilin-1 significantly reversed the THC-induced anti-inflammatory effects in MG-63 cells. These results suggested that CB2 is involved in the THC-induced anti-inflammation in LPS-stimulated MG-63 cells, and the anti-inflammation may be mediated by cofilin-1. Lei Yang, Fei-Fei Li, Yu-Chen Han, Bin Jia, and Yin Ding Copyright © 2015 Lei Yang et al. All rights reserved. Rapamycin Improves Palmitate-Induced ER Stress/NFκB Pathways Associated with Stimulating Autophagy in Adipocytes Wed, 14 Jan 2015 13:10:02 +0000 Obesity-induced endoplasmic reticulum (ER) stress and inflammation lead to adipocytes dysfunction. Autophagy helps to adapt to cellular stress and involves in regulating innate inflammatory response. In present study, we examined the activity of rapamycin, a mTOR kinase inhibitor, against endoplasmic reticulum stress and inflammation in adipocytes. An in vitro model was used in which 3T3-L1 adipocytes were preloaded with palmitate (PA) to generate artificial hypertrophy mature adipocytes. Elevated autophagy flux and increased number of autophagosomes were observed in response to PA and rapamycin treatment. Rapamycin attenuated PA-induced PERK and IRE1-associated UPR pathways, evidenced by decreased protein levels of eIF2α phosphorylation, ATF4, CHOP, and JNK phosphorylation. Inhibiting autophagy with chloroquine (CQ) exacerbated these ER stress markers, indicating the role of autophagy in ameliorating ER stress. In addition, cotreatment of CQ abolished the anti-ER stress effects of rapamycin, which confirms the effect of rapamycin on ERs is autophagy-dependent. Furthermore, rapamycin decreased PA-induced nuclear translocation of NFκB P65 subunit, thereby NFκB-dependent inflammatory cytokines MCP-1 and IL-6 expression and secretion. In conclusion, rapamycin attenuated PA-induced ER stress/NFκB pathways to counterbalance adipocytes stress and inflammation. The beneficial of rapamycin in this context partly depends on autophagy. Stimulating autophagy may become a way to attenuate adipocytes dysfunction. Jiajing Yin, Liping Gu, Yufan Wang, Nengguang Fan, Yuhang Ma, and Yongde Peng Copyright © 2015 Jiajing Yin et al. All rights reserved. ADAMTS-7 Exhibits Elevated Expression in Cartilage of Osteonecrosis of Femoral Head and Has a Positive Correlation with TNF-α and NF-κB P65 Wed, 14 Jan 2015 06:44:03 +0000 ADAMTS-7 has been reported to exaggerate cartilage degeneration and to be associated with TNF-α and NF-κB signaling pathway. In this study we compared the expression of ADAMTS-7, TNF-α, and Phospho-NF-κB in patients with femoral neck fracture (FNF) and osteonecrosis of femoral head (ONFH) at different stages. We found that expression of ADAMTS-7, TNF-α, and Phospho-NF-κB was significantly upregulated in ONFH patients’ articular cartilage and related to the pathogenesis of ONFH. Thus we conclude that ADAMTS-7 level appears to be positively associated with expression of TNF-α and Phospho-NF-κB P65 in cartilage, which may imply its association with cartilage destruction of ONFH. Jing-kun Li, Lei Cheng, Yun-peng Zhao, Ying-jun Guo, Yi Liu, Wei Zhang, Shuai-shuai Wang, Yuan-qiang Zhang, Xin Pan, and Lin Nie Copyright © 2015 Jing-kun Li et al. All rights reserved. Ocular Inflammation Tue, 13 Jan 2015 07:40:33 +0000 Valentín Huerva, Francisco J. Ascaso, and Andrzej Grzybowski Copyright © 2015 Valentín Huerva et al. All rights reserved. Proteasome Inhibitor Bortezomib Suppresses Nuclear Factor-Kappa B Activation and Ameliorates Eye Inflammation in Experimental Autoimmune Uveitis Mon, 12 Jan 2015 11:43:36 +0000 Bortezomib is a proteasome inhibitor used for hematologic cancer treatment. Since it can suppress NF-κB activation, which is critical for the inflammatory process, bortezomib has been found to possess anti-inflammatory activity. In this study, we evaluated the effect of bortezomib on experimental autoimmune uveitis (EAU) in mice and investigated the potential mechanisms related to NF-κB inactivation. High-dose bortezomib (0.75 mg/kg), low-dose bortezomib (0.15 mg/kg), or phosphate buffered saline was given after EAU induction. We found that the EAU is ameliorated by high-dose bortezomib treatment when compared with low-dose bortezomib or PBS treatment. The DNA-binding activity of NF-κB was suppressed and expression of several key inflammatory mediators including TNF-α, IL-1α, IL-1β, IL-12, IL-17, and MCP-1 was lowered in the high-dose bortezomib-treated group. These results suggest that proteasome inhibition is a promising treatment strategy for autoimmune uveitis. Sheng-Min Hsu, Chang-Hao Yang, Fang-Hsiu Shen, Shun-Hua Chen, Chia-Jhen Lin, and Chi-Chang Shieh Copyright © 2015 Sheng-Min Hsu et al. All rights reserved. Disturbances of Modulating Molecules (FOXP3, CTLA-4/CD28/B7, and CD40/CD40L) mRNA Expressions in the Orbital Tissue from Patients with Severe Graves’ Ophthalmopathy Mon, 12 Jan 2015 06:22:58 +0000 Purpose. To evaluate the relationship between the expression of orbital tissue mRNA for FOXP3, CTLA-4/CD28/CD80/CD86, and CD40/CD40 and the severity of Graves’ orbitopathy (GO). Material and Methods. Orbital tissue was obtained from 26 patients with GO, with mild () or severe GO (), and 7 healthy controls. The expression of mRNA of FOXP3, CTLA-4/CD28/CD80/CD86, CD40/CD40L was measured by RT-PCR. TCR and CD3 were evaluated by immunohistochemistry. Results. Higher mRNA for FoxP3 (relative expression: 1.4) and CD40 (1.27) and lower expression of CTLA-4 (0.61) were found in the GO tissues versus controls. In severe GO as compared to mild GO higher mRNA expression for FoxP3 (1.35) and CD40 (1.4) and lower expression for CTLA-4 (0.78), CD28 (0.62), and CD40L (0.56) were found. A positive correlation was found between FOXP3 mRNA and CD3 infiltration (, ). Conclusions. The enhanced FOXP3 mRNA expression in GO samples may suggest the dysfunction of FOXP3 cells in the severe GO. The diminished mRNA expression of CTLA-4 in severe GO may indicate inadequate T regulatory function. The enhanced mRNA expression of CD40 in severe GO and negative correlation to CRP mRNA may suggest their role in the active and inactive GO. Przemyslaw Pawlowski, Natalia Wawrusiewicz-Kurylonek, Anja Eckstein, Joanna Reszec, Wlodzimierz Luczynski, Kristian Johnson, Adam Kretowski, Alina Bakunowicz-Lazarczyk, Maria Gorska, Jacek Szamatowicz, Lech Chyczewski, and Janusz Mysliwiec Copyright © 2015 Przemyslaw Pawlowski et al. All rights reserved. Moderate Exercise Training Attenuates the Severity of Experimental Rodent Colitis: The Importance of Crosstalk between Adipose Tissue and Skeletal Muscles Mon, 05 Jan 2015 06:29:23 +0000 Although progress has been recently made in understanding of inflammatory bowel diseases (IBD), their etiology is unknown apart from several factors from adipose tissue and skeletal muscles such as cytokines, adipokines, and myokines were implicated in the pathogenesis of ulcerative colitis. We studied the effect high-fat diet (HFD; cholesterol up to 70%), low-fat diet (LFD; cholesterol up to 10%), and the normal diet (total fat up to 5%) in rats with TNBS colitis forced to treadmill running exercise (5 days/week) for 6 weeks. In nonexercising HFD rats, the area of colonic damage, colonic tissue weight, the plasma IL-1β, TNF-α, TWEAK, and leptin levels, and the expression of IL-1β-, TNF-α-, and Hif1α mRNAs were significantly increased and a significant fall in plasma adiponectin and irisin levels was observed as compared to LFD rats. In HFD animals, the exercise significantly accelerated the healing of colitis, raised the plasma levels of IL-6 and irisin, downregulated the expression of IL-1β, TNF-α, and Hif1α, and significantly decreased the plasma IL-1β, TNF α, TWEAK, and leptin levels. We conclude that HFD delays the healing of colitis in trained rats via decrease in CBF and plasma IL-1β, TNF-α, TWEAK, and leptin levels and the release of protective irisin. Jan Bilski, Agnieszka I. Mazur-Bialy, Bartosz Brzozowski, Marcin Magierowski, Katarzyna Jasnos, Gracjana Krzysiek-Maczka, Katarzyna Urbanczyk, Agata Ptak-Belowska, Malgorzata Zwolinska-Wcislo, Tomasz Mach, and Tomasz Brzozowski Copyright © 2015 Jan Bilski et al. All rights reserved. Neonatal Sepsis and Inflammatory Mediators Tue, 30 Dec 2014 08:35:21 +0000 Neonatal sepsis is a major cause of morbidity and mortality and its signs and symptoms are nonspecific, which makes the diagnosis difficult. The routinely used laboratory tests are not effective methods of analysis, as they are extremely nonspecific and often cause inappropriate use of antibiotics. Sepsis is the result of an infection associated with a systemic inflammatory response with production and release of a wide range of inflammatory mediators. Cytokines are potent inflammatory mediators and their serum levels are increased during infections, so changes from other inflammatory effector molecules may occur. Although proinflammatory and anti-inflammatory cytokines have been identified as probable markers of neonatal infection, in order to characterize the inflammatory response during sepsis, it is necessary to analyze a panel of cytokines and not only the measurement of individual cytokines. Measurements of inflammatory mediators bring new options for diagnosing and following up neonatal sepsis, thus enabling early treatment and, as a result, increased neonatal survival. By taking into account the magnitude of neonatal sepsis, the aim of this review is to address the role of cytokines in the pathogenesis of neonatal sepsis and its value as a diagnostic criterion. Juliana Reis Machado, Danilo Figueiredo Soave, Marcos Vinícius da Silva, Liliana Borges de Menezes, Renata Margarida Etchebehere, Maria Luiza Gonçalves dos Reis Monteiro, Marlene Antônia dos Reis, Rosana Rosa Miranda Corrêa, and Mara Rúbia Nunes Celes Copyright © 2014 Juliana Reis Machado et al. All rights reserved. Quercetin Protects against Obesity-Induced Skeletal Muscle Inflammation and Atrophy Sun, 28 Dec 2014 10:12:56 +0000 Skeletal muscle inflammation and atrophy are closely associated with metabolic impairment such as insulin resistance. Quercetin, a natural polyphenol flavonoid, is known to elicit anti-inflammatory and antioxidant activities. In this study, we investigated its effect on obesity-induced skeletal muscle inflammation and atrophy in mice. Male C57BL/6 mice were fed a regular diet, a high-fat diet (HFD), and an HFD supplemented with quercetin for nine weeks. Quercetin reduced levels of inflammatory cytokines and macrophage accumulation in the skeletal muscle of the HFD-fed obese mice. It also reduced transcript and protein levels of the specific atrophic factors, Atrogin-1 and MuRF1, in the skeletal muscle of the HFD-fed obese mice, and protected against the reduction of muscle mass and muscle fiber size. In vitro, quercetin markedly diminished transcript levels of inflammatory receptors and activation of their signaling molecules (ERK, p38 MAPK, and NF-B) in cocultured myotubes/macrophages, and this was accompanied by reduced expression of the atrophic factors. Together, these findings suggest that quercetin reduces obesity-induced skeletal muscle atrophy by inhibiting inflammatory receptors and their signaling pathway. Quercetin may be useful for preventing obesity-induced muscle inflammation and sarcopenia. Ngoc Hoan Le, Chu-Sook Kim, Taesun Park, Jung Han Yoon Park, Mi-Kyung Sung, Dong Gun Lee, Sun-Myung Hong, Suck-Young Choe, Tsuyoshi Goto, Teruo Kawada, and Rina Yu Copyright © 2014 Ngoc Hoan Le et al. All rights reserved. The Influence of Ouabain on Human Dendritic Cells Maturation Sun, 28 Dec 2014 00:10:27 +0000 Although known as a Na,K-ATPase inhibitor, several other cellular and systemic actions have been ascribed to the steroid Ouabain (Oua). Particularly in the immune system, our group showed that Ouabain acts on decreasing lymphocyte proliferation, synergizing with glucocorticoids in spontaneous thymocyte apoptosis, and also lessening CD14 expression and blocking CD16 upregulation on human monocytes. However, Ouabain effects on dendritic cells (DCs) were not explored so far. Considering the peculiar plasticity and the importance of DCs in immune responses, the aim of our study was to investigate DC maturation under Ouabain influence. To generate immature DCs, human monocytes were cultured with IL-4 and GM-CSF (5 days). To investigate Ouabain role on DC activation, DCs were stimulated with TNF-α for 48 h in the presence or absence of Ouabain. TNF-induced CD83 expression and IL-12 production were abolished in DCs incubated with 100 nM Ouabain, though DC functional capacity concerning lymphocyte activation remained unaltered. Nevertheless, TNF-α-induced antigen capture downregulation, another maturation marker, occurred even in the presence of Ouabain. Besides, Ouabain increased HLA-DR and CD86 expression, whereas CD80 expression was maintained. Collectively, our results suggest that DCs respond to Ouabain maturating into a distinct category, possibly contributing to the balance between immunity and tolerance. C. R. Nascimento, R. C. Valente, J. Echevarria-Lima, C. F. L. Fontes, L. de Araujo-Martins, E. G. Araujo, and V. M. Rumjanek Copyright © 2014 C. R. Nascimento et al. All rights reserved. Herbal Medicines for Inflammatory Diseases Wed, 24 Dec 2014 07:51:38 +0000 Seong-Gyu Ko, Chang Shik Yin, Bing Du, and KyoungHyun Kim Copyright © 2014 Seong-Gyu Ko et al. All rights reserved. Acute Exercise-Induced Response of Monocyte Subtypes in Chronic Heart and Renal Failure Mon, 22 Dec 2014 07:42:56 +0000 Purpose. Monocytes (Mon1-2-3) play a substantial role in low-grade inflammation associated with high cardiovascular morbidity and mortality of patients with chronic kidney disease (CKD) and chronic heart failure (CHF). The effect of an acute exercise bout on monocyte subsets in the setting of systemic inflammation is currently unknown. This study aims (1) to evaluate baseline distribution of monocyte subsets in CHF and CKD versus healthy subjects (HS) and (2) to evaluate the effect of an acute exercise bout. Exercise-induced IL-6 and MCP-1 release are related to the Mon1-2-3 response. Methods. Twenty CHF patients, 20 CKD patients, and 15 HS were included. Before and after a maximal cardiopulmonary exercise test, monocyte subsets were quantified by flow cytometry: CD14++CD16−CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2), and CD14+CD16++CCR2− (Mon3). Serum levels of IL-6 and MCP-1 were determined by ELISA. Results. Baseline distribution of Mon1-2-3 was comparable between the 3 groups. Following acute exercise, %Mon2 and %Mon3 increased significantly at the expense of a decrease in %Mon1 in HS and in CKD. This response was significantly attenuated in CHF (). In HS only, MCP-1 levels increased following exercise; IL-6 levels were unchanged. Circulatory power was a strong and independent predictor of the changes in Mon1 (, ) and Mon3 (, ); and baseline LVEF of the change in Mon2 (, ). Conclusion. The response of monocytes to acute exercise is characterized by an increase in proangiogenic and proinflammatory Mon2 and Mon3 at the expense of phagocytic Mon1. This exercise-induced monocyte subset response is mainly driven by hemodynamic changes and not by preexistent low-grade inflammation. Amaryllis H. Van Craenenbroeck, Katrijn Van Ackeren, Vicky Y. Hoymans, Johan Roeykens, Gert A. Verpooten, Christiaan J. Vrints, Marie M. Couttenye, and Emeline M. Van Craenenbroeck Copyright © 2014 Amaryllis H. Van Craenenbroeck et al. All rights reserved. Brain-Derived Neurotrophic Factor in Chronic Periodontitis Sun, 21 Dec 2014 09:30:49 +0000 Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family. Outside the nervous system, BDNF has been shown to be expressed in various nonneural tissues, such as periodontal ligament, dental pulp, and odontoblasts. Although a role for BDNF in periodontal regeneration has been suggested, a function for BDNF in periodontal disease has not yet been studied. The aim of this study was to analyze the BDNF levels in periodontal tissues of patients with chronic periodontitis (CP) and periodontally healthy controls (HC). All subjects were genotyped for the rs4923463 and rs6265 BDNF polymorphisms. Periodontal tissues were collected for ELISA, myeloperoxidase (MPO), and microscopic analysis from 28 CP patients and 29 HC subjects. BDNF levels were increased in CP patients compared to HC subjects. A negative correlation was observed when analyzing concentration of BDNF and IL-10 in inflamed periodontium. No differences in frequencies of BDNF genotypes between CP and HC subjects were observed. However, BDNF genotype GG was associated with increased levels of BDNF, TNF-α, and CXCL10 in CP patients. In conclusion, BDNF seems to be associated with periodontal disease process, but the specific role of BDNF still needs to be clarified. Jôice Dias Corrêa, Daniele Sirineu Pereira, Mila Fernandes Moreira Madeira, Celso Martins Queiroz-Junior, Danielle Glória Souza, Mauro Martins Teixeira, José Eustáquio Costa, Antônio Lúcio Teixeira, and Tarcília Aparecida da Silva Copyright © 2014 Jôice Dias Corrêa et al. All rights reserved. The Roles of CD147 and/or Cyclophilin A in Kidney Diseases Wed, 17 Dec 2014 07:42:37 +0000 CD147 is a widely expressed integral plasma membrane glycoprotein and has been involved in a variety of physiological and pathological activities in combination with different partners, including cyclophilins, caveolin-1, monocarboxylate transporters, and integrins. Recent data demonstrate that both CyPA and CD147 significantly contribute to renal inflammation, acute kidney injury, renal fibrosis, and renal cell carcinoma. Here we review the current understanding of cyclophilin A and CD147 expression and functions in kidney diseases and potential implications for treatment of kidney diseases. Xin Qu, Chunting Wang, Jicheng Zhang, Guoqiang Qie, and Jianxin Zhou Copyright © 2014 Xin Qu et al. All rights reserved. On the Significance of New Biochemical Markers for the Diagnosis of Premature Labour Mon, 08 Dec 2014 13:09:43 +0000 Preterm labour is defined as a birth taking place between 22nd and 37th weeks of gestation. Despite numerous studies on the aetiology and pathogenesis of preterm labour, its very cause still remains unclear. The importance of the cytokines and acute inflammation in preterm labour aetiology is nowadays well-proven. However, chronic inflammation as an element of the pathogenesis of premature labour is still unclear. This paper presents a literature review on the damage-associated molecular patterns (DAMPs), receptors for advanced glycation end products (RAGE), negative soluble isoforms of RAGE, chemokine-stromal cell-derived factor-1 (SDF-1) and one of the adipokines, resistin, in the pathogenesis of preterm labour. We conclude that the chronic inflammatory response can play a much more important role in the pathogenesis of preterm delivery than the acute one. Rafał Rzepka, Barbara Dołęgowska, Aleksandra Rajewska, and Sebastian Kwiatkowski Copyright © 2014 Rafał Rzepka et al. All rights reserved.