Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. A Novel Oxidative Stress Mediator in Acute Appendicitis: Thiol/Disulphide Homeostasis Tue, 23 Aug 2016 09:58:21 +0000 Aim. To investigate the role of a novel oxidative stress marker, thiol/disulphide homeostasis, in patients diagnosed with acute appendicitis (AA). Methods. In this study, seventy-one (43 male and 28 female) patients diagnosed with AA and 71 (30 male and 41 female) healthy volunteers were included. Age, gender, body mass index (BMI), haemoglobin (Hb), white blood cell (WBC), c-reactive protein (CRP), and thiol/disulphide homeostasis parameters (native thiol, total thiol, disulphide, disulphide/native thiol, native thiol/total thiol, and disulphide/total thiol ratios) were compared between the groups. Thiol/disulphide homeostasis was determined by a newly developed method by Erel and Neselioglu. Results. The native thiol, total thiol, and the native thiol/total thiol ratio levels were statistically significantly decreased in the AA compared with the control group (). Disulphide level and the ratios of disulphide/native thiol and disulphide/total thiol were higher in the AA group than in the control group (). There was a negative correlation of CRP with native thiol, total thiol, and native thiol/total thiol ratio while there was a positive correlation of CRP with disulphide/native thiol and disulphide/total thiol in the AA group. In the stepwise regression model, risk factors as disulphide/native thiol (OR = 1.368; ) and CRP (OR = 1.635; ) were determined as predictors of perforated appendicitis compared to the nonperforated group. Conclusion. This is the first study examining the thiol/disulphide homeostasis as a diagnostic aid in AA and establishing thiol/disulphide homeostatis balance shifted towards the disulphide formation due to thiol oxidation. Further studies are needed to optimize the use of this novel oxidative stress marker in AA. Sefa Ozyazici, Faruk Karateke, Umit Turan, Adnan Kuvvetli, Huseyin Kilavuz, Burak Karakaya, Pınar Ozaltun, Murat Alısık, and Ozcan Erel Copyright © 2016 Sefa Ozyazici et al. All rights reserved. Protective Effect of Amphipterygium adstringens Extract on Dextran Sulphate Sodium-Induced Ulcerative Colitis in Mice Sun, 21 Aug 2016 12:38:51 +0000 Amphipterygium adstringens is an endemic species in Mexico commonly known as “cuachalalate.” Healers to treat gastritis, gastric ulcers, and gastrointestinal cancer have traditionally used the bark. We investigated the effects of alcoholic extract of A. adstringens (AaEE) in DSS-induced colitis in mice. The protective effect of AaEE was determined at 200 mg/kg by oral gavage for 10 days. We determine the effect of AaEE on clinical features (disease activity index), antioxidants, anti-inflammatory, and immunomodulatory activities in relation to the activity of SOD, CAT, and GPx, levels of proinflammatory cytokines, and changes both macroscopic and microscopic of the colonic mucosa. AaEE significantly reduced the inflammation of colon and significantly increased SOD and GPx activities. AaEE also significantly decreased TNF-α, IFN-γ, and IL-1β cytokine levels compared to DSS-treated mice and reduced both infiltration of inflammatory cells and the mucosal damage in colon. The results suggested the protective potential of AaEE in DSS-induced colitis and this might be attributed to its phytochemicals compounds that have been found to induce a wide spectrum of activities such as reduction in oxidative stress, suppression of inflammation, modulating numerous signal transduction pathways, and induction of apoptosis. The findings of this study suggest that AaEE has substantial potential for the treatment of inflammatory colitis. Mario Rodriguez-Canales, Ruben Jimenez-Rivas, Maria Margarita Canales-Martinez, Ana Judith Garcia-Lopez, Nelly Rivera-Yañez, Oscar Nieto-Yañez, Yadira Ledesma-Soto, Luvia Enid Sanchez-Torres, Miriam Rodriguez-Sosa, Luis Ignacio Terrazas, and Marco Aurelio Rodriguez-Monroy Copyright © 2016 Mario Rodriguez-Canales et al. All rights reserved. Kidney Expression of Toll Like Receptors in Lupus Nephritis: Quantification and Clinicopathological Correlations Sun, 21 Aug 2016 11:28:26 +0000 Objective. The study aimed at locating and quantifying Toll Like Receptor (TLR) 3, 7, 8, and 9 expression in kidney of patients with lupus nephritis (LN) and correlating them with clinicopathological features. Methods. Kidney sections from 26 LN patients and 4 controls were analyzed by immunohistochemistry using anti-human TLR3, TLR7, TLR8, and TLR9 polyclonal antibodies; the number of TLR-positive nuclei/mm2 was evaluated on digitalized images. Results. Compared to controls, LN showed a significantly higher amount of glomerular and tubulointerstitial TLR9 ( and ), whole and tubulointerstitial TLR3 ( and ), and a higher tubulointerstitial TLR7 (). TLR9 positively correlated with activity index () and tubular TLR7 with chronicity index (). TLR9 positively correlated with Renal-SLEDAI (). Conclusions. This is the first study quantifying kidney expressions of TLRs in LN patients; the results show an overexpression of TLR3, TLR7, and TLR9 and demonstrate a correlation with clinicopathological indices supporting a role of these mediators in the pathogenesis of LN. Fabrizio Conti, Francesca Romana Spinelli, Simona Truglia, Francesca Miranda, Cristiano Alessandri, Fulvia Ceccarelli, Michele Bombardieri, Konstantinos Giannakakis, and Guido Valesini Copyright © 2016 Fabrizio Conti et al. All rights reserved. The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation Thu, 18 Aug 2016 16:06:52 +0000 State of tumor microenvironment (TME) is closely linked to regulation of tumor growth and progression affecting the final outcome, refractoriness, and relapse of disease. Interactions of tumor, immune, and mesenchymal stromal/stem cells (MSCs) have been recognized as crucial for understanding tumorigenesis. Due to their outstanding features, stem cell-like properties, capacity to regulate immune response, and dynamic functional phenotype dependent on microenvironmental stimuli, MSCs have been perceived as important players in TME. Signals provided by tumor-associated chronic inflammation educate MSCs to alter their phenotype and immunomodulatory potential in favor of tumor-biased state of MSCs. Adjustment of phenotype to TME and acquisition of tumor-promoting ability by MSCs help tumor cells in maintenance of permissive TME and suppression of antitumor immune response. Potential utilization of MSCs in treatment of tumor is based on their inherent ability to home tumor tissue that makes them suitable delivery vehicles for immune-stimulating factors and vectors for targeted antitumor therapy. Here, we review data regarding intrusive effects of inflammatory TME on MSCs capacity to affect tumor development through modification of their phenotype and interactions with immune system. Drenka Trivanović, Jelena Krstić, Ivana Okić Djordjević, Slavko Mojsilović, Juan Francisco Santibanez, Diana Bugarski, and Aleksandra Jauković Copyright © 2016 Drenka Trivanović et al. All rights reserved. TLR Signalling Pathways Diverge in Their Ability to Induce PGE2 Thu, 18 Aug 2016 08:12:05 +0000 PGE2 is a lipid mediator abundantly produced in inflamed tissues that exerts relevant immunoregulatory functions. Dendritic cells (DCs) are key players in the onset and shaping of the inflammatory and immune responses and, as such, are well known PGE2 targets. By contrast, the precise role of human DCs in the production of PGE2 is poorly characterized. Here, we asked whether different ligands of Toll-like receptors (TLRs), a relevant family of pathogen-sensing receptors, could induce PGE2 in human DCs. The only active ligands were LPS (TLR4 ligand) and R848 (TLR7-8 ligand) although all TLRs, but TLR9, were expressed and functional. While investigating the molecular mechanisms hindering the release of PGE2, our experiments highlighted so far oversight differences in TLR signalling pathways in terms of MAPK and NF-κB activation. In addition, we identified that the PGE2-limiting checkpoint downstream TLR3, TLR5, and TLR7 was a defect in COX2 induction, while TLR1/2 and TLR2/6 failed to mobilize arachidonic acid, the substrate for the COX2 enzyme. Finally, we demonstrated the in vivo expression of PGE2 by myeloid CD11c+ cells, documenting a role for DCs in the production of PGE2 in human inflamed tissues. Valentina Salvi, Xenia Vaira, Veronica Gianello, William Vermi, Mattia Bugatti, Silvano Sozzani, and Daniela Bosisio Copyright © 2016 Valentina Salvi et al. All rights reserved. Exaggerated IL-15 and Altered Expression of foxp3+ Cell-Derived Cytokines Contribute to Enhanced Colitis in Nlrp3−/− Mice Wed, 17 Aug 2016 16:48:53 +0000 The pathogenesis of Crohn’s disease (CD) involves defects in the innate immune system, impairing responses to microbes. Studies have revealed that mutations NLRP3 are associated with CD. We reported previously that Nlrp3−/− mice were more susceptible to colitis and exhibited reduced colonic IL-10 expression. In the current study, we sought to determine how the loss of NLRP3 might be altering the function of regulatory T cells, a major source of IL-10. Colitis was induced in wild-type (WT) and Nlrp3−/− mice by treatment with dextran sulphate sodium (DSS). Lamina propria (LP) cells were assessed by flow cytometry and cytokine expression was assessed. DSS-treated Nlrp3−/− mice exhibited increased numbers of colonic foxp3+ T cells that expressed significantly lower levels of IL-10 but increased IL-17. This was associated with increased expression of colonic IL-15 and increased surface expression of IL-15 on LP dendritic cells. Neutralizing IL-15 in Nlrp3−/− mice attenuated the severity of colitis, decreased the number of colonic foxp3+ cells, and reduced the colonic expression of IL-12p40 and IL-17. These data suggest that the NLRP3 inflammasome can regulate intestinal inflammation through noncanonical mechanisms, providing additional insight as to how NLRP3 variants may contribute to the pathogenesis of CD. Simon A. Hirota, Aito Ueno, Sarah E. Tulk, Helen M. Becker, L. Patrick Schenck, Mireille S. Potentier, Yan Li, Subrata Ghosh, Daniel A. Muruve, Justin A. MacDonald, and Paul L. Beck Copyright © 2016 Simon A. Hirota et al. All rights reserved. Interferon Tau Affects Mouse Intestinal Microbiota and Expression of IL-17 Wed, 17 Aug 2016 14:30:06 +0000 This study was conducted to explore the effects of interferon tau (IFNT) on the intestinal microbiota and expression of interleukin 17 (IL-17) in the intestine of mice. IFNT supplementation increased microbial diversity in the jejunum and ileum but decreased microbial diversity in the feces. IFNT supplementation influenced the composition of the intestinal microbiota as follows: (1) decreasing the percentage of Firmicutes and increasing Bacteroidetes in the jejunum and ileum; (2) enhancing the percentage of Firmicutes but decreasing Bacteroidetes in the colon and feces; (3) decreasing Lactobacillus in the jejunum and ileum; (4) increasing the percentage of Blautia, Bacteroides, Alloprevotella, and Lactobacillus in the colon; and (5) increasing the percentage of Lactobacillus, Bacteroides, and Allobaculum, while decreasing Blautia in the feces. Also, IFNT supplementation decreased the expression of IL-17 in the intestines of normal mice and of an intestinal pathogen infected mice. In conclusion, IFNT supplementation modulates the intestinal microbiota and intestinal IL-17 expression, indicating the applicability of IFNT to treat the intestinal diseases involving IL-17 expression and microbiota. Wenkai Ren, Shuai Chen, Liwen Zhang, Gang Liu, Tarique Hussain, Xiao Hao, Jie Yin, Jielin Duan, Bie Tan, Guoyao Wu, Fuller W. Bazer, and Yulong Yin Copyright © 2016 Wenkai Ren et al. All rights reserved. Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis Wed, 17 Aug 2016 14:06:39 +0000 Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized with plus complete Freund’s adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role for mMCP-4 in the early inflammatory phases of the disease in a mouse model of MS. Louisane Desbiens, Catherine Lapointe, Marjan Gharagozloo, Shaimaa Mahmoud, Gunnar Pejler, Denis Gris, and Pedro D’Orléans-Juste Copyright © 2016 Louisane Desbiens et al. All rights reserved. TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation Wed, 17 Aug 2016 12:05:33 +0000 Renal fibrosis, irrespective of its etiology, is a final common stage of almost all chronic kidney diseases. Increased apoptosis, epithelial-to-mesenchymal transition, and inflammatory cell infiltration characterize the injured kidney. On the molecular level, transforming growth factor-β1 (TGF-β1)-Smad3 signaling pathway plays a central role in fibrotic kidney disease. Recent findings indicate the prominent role of microRNAs, small noncoding RNA molecules that inhibit gene expression through the posttranscriptional repression of their target mRNAs, in different pathologic conditions, including renal pathophysiology. miR-21 was also shown to play a dynamic role in inflammatory responses and in accelerating injury responses to promote organ failure and fibrosis. Understanding the cellular and molecular bases of miR-21 involvement in the pathogenesis of kidney diseases, including inflammatory reaction, could be crucial for their early diagnosis. Moreover, the possibility of influencing miR-21 level by specific antagomirs may be considered as an approach for treatment of renal diseases. Agnieszka Loboda, Mateusz Sobczak, Alicja Jozkowicz, and Jozef Dulak Copyright © 2016 Agnieszka Loboda et al. All rights reserved. Diet-Intestinal Microbiota Axis in Osteoarthritis: A Possible Role Wed, 17 Aug 2016 06:31:04 +0000 Intestinal microbiota is highly involved in host physiology and pathology through activity of the microbiome and its metabolic products. Osteoarthritis (OA) is a common form of arthritis characterized by articular cartilage destruction and osteophyte formation. Although various person-level risk factors, such as age, sex, and obesity, have been proposed for the pathogenesis of OA, the underlying links between these person-level factors and OA are still enigmatic. Based on the current understanding in the crosstalk between intestinal microbiota and these risk factors, intestinal microbiota could be considered as a major hidden risk factor that provides a unifying mechanism to explain the involvement of these person-level risk factors in OA. Yusheng Li, Wei Luo, Zhenhan Deng, and Guanghua Lei Copyright © 2016 Yusheng Li et al. All rights reserved. Identification of a Novel lincRNA-p21-miR-181b-PTEN Signaling Cascade in Liver Fibrosis Tue, 16 Aug 2016 08:14:22 +0000 Previously, we found that long intergenic noncoding RNA-p21 (lincRNA-p21) inhibits hepatic stellate cell (HSC) activation and liver fibrosis via p21. However, the underlying mechanism of the antifibrotic role of lincRNA-p21 in liver fibrosis remains largely unknown. Here, we found that lincRNA-p21 expression was significantly downregulated during liver fibrosis. In LX-2 cells, the reduction of lincRNA-p21 induced by TGF-β1 was in a dose- and time-dependent manner. lincRNA-p21 expression was reduced in liver tissues from patients with liver cirrhosis when compared with that of healthy controls. Notably, lincRNA-p21 overexpression contributed to the suppression of HSC activation. lincRNA-p21 suppressed HSC proliferation and induced a significant reduction in α-SMA and type I collagen. All these effects induced by lincRNA-p21 were blocked down by the loss of PTEN, suggesting that lincRNA-p21 suppressed HSC activation via PTEN. Further study demonstrated that microRNA-181b (miR-181b) was involved in the effects of lincRNA-p21 on HSC activation. The effects of lincRNA-p21 on PTEN expression and HSC activation were inhibited by miR-181b mimics. We demonstrated that lincRNA-p21 enhanced PTEN expression by competitively binding miR-181b. In conclusion, our results disclose a novel lincRNA-p21-miR-181b-PTEN signaling cascade in liver fibrosis and suggest lincRNA-p21 as a promising molecular target for antifibrosis therapy. Fujun Yu, Zhongqiu Lu, Bicheng Chen, Peihong Dong, and Jianjian Zheng Copyright © 2016 Fujun Yu et al. All rights reserved. Novel Role of Endogenous Catalase in Macrophage Polarization in Adipose Tissue Mon, 15 Aug 2016 12:42:07 +0000 Macrophages are important components of adipose tissue inflammation, which results in metabolic diseases such as insulin resistance. Notably, obesity induces a proinflammatory phenotypic switch in adipose tissue macrophages, and oxidative stress facilitates this switch. Thus, we examined the role of endogenous catalase, a key regulator of oxidative stress, in the activity of adipose tissue macrophages in obese mice. Catalase knockout (CKO) exacerbated insulin resistance, amplified oxidative stress, and accelerated macrophage infiltration into epididymal white adipose tissue in mice on normal or high-fat diet. Interestingly, catalase deficiency also enhanced classical macrophage activation (M1) and inflammation but suppressed alternative activation (M2) regardless of diet. Similarly, pharmacological inhibition of catalase activity using 3-aminotriazole induced the same phenotypic switch and inflammatory response in RAW264.7 macrophages. Finally, the same phenotypic switch and inflammatory responses were observed in primary bone marrow-derived macrophages from CKO mice. Taken together, the data indicate that endogenous catalase regulates the polarization of adipose tissue macrophages and thereby inhibits inflammation and insulin resistance. Ye Seul Park, Md Jamal Uddin, Lingjuan Piao, Inah Hwang, Jung Hwa Lee, and Hunjoo Ha Copyright © 2016 Ye Seul Park et al. All rights reserved. Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance? Sun, 14 Aug 2016 11:43:19 +0000 Inflammation is a protective response of the organism to tissue injury or infection. It occurs when the immune system recognizes Pathogen-Associated Molecular Patterns (PAMPs) or Damage-Associated Molecular Pattern (DAMPs) through the activation of Pattern Recognition Receptors. This initiates a variety of signalling events that conclude in the upregulation of proinflammatory molecules, which initiate an appropriate immune response. This response is tightly regulated since any aberrant activation of immune responses would have severe pathological consequences such as sepsis or chronic inflammatory and autoimmune diseases. Accumulative evidence shows that the ubiquitin system, and in particular ubiquitin-specific isopeptidases also known as deubiquitinases (DUBs), plays crucial roles in the control of these immune pathways. In this review we will give an up-to-date overview on the role of DUBs in the NF-κB pathway and inflammasome activation, two intrinsically related events triggered by activation of the membrane TLRs as well as the cytosolic NOD and NLR receptors. Modulation of DUB activity by small molecules has been proposed as a way to control dysregulation or overactivation of these key players of the inflammatory response. We will also discuss the advances and challenges of a potential use of DUBs as therapeutic targets in inflammatory pathologies. Gloria Lopez-Castejon and Mariola J. Edelmann Copyright © 2016 Gloria Lopez-Castejon and Mariola J. Edelmann. All rights reserved. The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is “Inflammation” Always Inflammation? Thu, 11 Aug 2016 16:13:36 +0000 Inflammation is a response to infections or tissue injuries. Inflammation was once defined by clinical signs, later by the presence of leukocytes, and nowadays by expression of “proinflammatory” cytokines and chemokines. But leukocytes and cytokines often have rather anti-inflammatory, proregenerative, and homeostatic effects. Is there a need to redefine “inflammation”? In this review, we discuss the functions of “inflammatory” mediators/regulators of the innate immune system that determine tissue environments to fulfill the need of the tissue while regaining homeostasis after injury. Onkar P. Kulkarni, Julia Lichtnekert, Hans-Joachim Anders, and Shrikant R. Mulay Copyright © 2016 Onkar P. Kulkarni et al. All rights reserved. Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation Thu, 11 Aug 2016 09:50:47 +0000 Since the discovery of the endocannabinoid system consisting of cannabinoid receptors, endogenous ligands, and biosynthetic and metabolizing enzymes, interest has been renewed in investigating the promise of cannabinoids as therapeutic agents. Abundant evidence indicates that cannabinoids modulate immune responses. An inflammatory response is triggered when innate immune cells receive a danger signal provided by pathogen- or damage-associated molecular patterns engaging pattern-recognition receptors. Toll-like receptor family members are prominent pattern-recognition receptors expressed on innate immune cells. Cannabinoids suppress Toll-like receptor-mediated inflammatory responses. However, the relationship between the endocannabinoid system and innate immune system may not be one-sided. Innate immune cells express cannabinoid receptors and produce endogenous cannabinoids. Hence, innate immune cells may play a role in regulating endocannabinoid homeostasis, and, in turn, the endocannabinoid system modulates local inflammatory responses. Studies designed to probe the interaction between the innate immune system and the endocannabinoid system may identify new potential molecular targets in developing therapeutic strategies for chronic inflammatory diseases. This review discusses the endocannabinoid system and Toll-like receptor family and evaluates the interaction between them. Kathleen L. McCoy Copyright © 2016 Kathleen L. McCoy. All rights reserved. Association between IgG4 Autoantibody and Complement Abnormalities in Systemic Lupus Erythematosus Thu, 11 Aug 2016 07:25:48 +0000 In order to investigate the association between IgG4 autoantibody and complement abnormalities in systemic lupus erythematosus (SLE), 72 newly diagnosed SLE patients, 67 rheumatoid arthritis (RA) patients, and 41 healthy normals were employed. Serum levels of antinuclear IgG4 and IgG4-specific IgM-rheumatoid factor (RF) were measured, and the correlations between serum levels of antinuclear IgG4 and several clinical parameters were analyzed. Also, the levels of IgG subclasses, C1q, and C3 deposition in lupus nephritis (LN) were detected. The results showed that serum levels of antinuclear IgG4 were higher in SLE patients relative to healthy normals (). Serum levels of antinuclear IgG4 in SLE patients were positively correlated with serum levels of total IgG4, albumin, and C3 (, ; , ; and , , resp.) and negatively correlated with 24-hour urinary protein (, ). Serum levels of IgG4-specific IgM-RF were higher in RA patients than in SLE patients (). Also, the ratio of the deposition score for IgG4/(IgG1 + IgG2 + IgG3 + IgG4) was negatively correlated with the score for C1q and C3 deposition in LN (, ; , , resp.). In summary, the IgG4 autoantibody may dampen the inflammatory response in SLE, thus maybe providing a novel therapeutic target for SLE. Qingjun Pan, Linjie Guo, Jing Wu, Jun Cai, Huanjin Liao, Qiaofen Lan, Yanxia Peng, Yiming He, and Hua-feng Liu Copyright © 2016 Qingjun Pan et al. All rights reserved. 15-Lipoxygenase-1 Is Involved in the Effects of Atorvastatin on Endothelial Dysfunction Wed, 10 Aug 2016 13:37:21 +0000 Statins exert pleiotropic effects on endothelial cells in addition to lowering cholesterol. 15-Lipoxygenase-1 (ALOX15) has been implicated in vascular inflammation and disease. The relationship between atorvastatin and ALOX15 was investigated using a rat carotid artery balloon-injury model. Hematoxylin and eosin (HE) staining showed that ALOX15 overexpression increased the thickness of the intima-media (IMT). Immunohistochemistry and western blotting showed that atorvastatin increased the expression of cellular adhesion molecules (CAMs) but decreased the expression of endothelial nitric oxide synthase (eNOS); these effects of atorvastatin were blocked by ALOX15 overexpression. In human umbilical venous endothelial cells (HUVECs), silencing of ALOX15 enhanced the effects of atorvastatin on endothelial function. Expression levels of CAMs and Akt/eNOS/NO under oxidized low-density lipoprotein (ox-LDL) stimulation were modulated by ALOX15 inhibitor and ALOX15 small interfering RNA (siRNA). Atorvastatin abolished the activation of nuclear factor-kappa B (NF-κB) induced by ox-LDL. Exposure to ox-LDL induced upregulation of ALOX15 in HUVECs, but this effect was partially abolished by atorvastatin or the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). These results demonstrate that regulation of ALOX15 expression might be involved in the effects of atorvastatin on endothelial dysfunction. Peng Zhang, Xin Xing, Chunxiao Hu, Hui Yu, Qian Dong, Guanglei Chang, Shu Qin, Jian Liu, and Dongying Zhang Copyright © 2016 Peng Zhang et al. All rights reserved. Epigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases Wed, 10 Aug 2016 07:36:53 +0000 Systemic inflammatory rheumatic diseases are considered as autoimmune diseases, meaning that the balance between recognition of pathogens and avoidance of self-attack is impaired and the immune system attacks and destroys its own healthy tissue. Treatment with conventional Disease Modifying Antirheumatic Drugs (DMARDs) and/or Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) is often associated with various adverse reactions due to unspecific and toxic properties of those drugs. Although biologic drugs have largely improved the outcome in many patients, such drugs still pose significant problems and fail to provide a solution to all patients. Therefore, development of more effective treatments and improvements in early diagnosis of rheumatic diseases are badly needed in order to increase patient’s functioning and quality of life. The reversible nature of epigenetic mechanisms offers a new class of drugs that modulate the immune system and inflammation. In fact, epigenetic drugs are already in use in some types of cancer or cardiovascular diseases. Therefore, epigenetic-based therapeutics that control autoimmunity and chronic inflammatory process have broad implications for the pathogenesis, diagnosis, and management of rheumatic diseases. This review summarises the latest information about potential therapeutic application of epigenetic modification in targeting immune abnormalities and inflammation of rheumatic diseases. Marzena Ciechomska and Steven O’Reilly Copyright © 2016 Marzena Ciechomska and Steven O’Reilly. All rights reserved. Cross-Linking Mast Cell Specific Gangliosides Stimulates the Release of Newly Formed Lipid Mediators and Newly Synthesized Cytokines Mon, 08 Aug 2016 16:58:02 +0000 Mast cells are immunoregulatory cells that participate in inflammatory processes. Cross-linking mast cell specific GD1b derived gangliosides by mAbAA4 results in partial activation of mast cells without the release of preformed mediators. The present study examines the release of newly formed and newly synthesized mediators following ganglioside cross-linking. Cross-linking the gangliosides with mAbAA4 released the newly formed lipid mediators, prostaglandins D2 and E2, without release of leukotrienes B4 and C4. The effect of cross-linking these gangliosides on the activation of enzymes in the arachidonate cascade was then investigated. Ganglioside cross-linking resulted in phosphorylation of cytosolic phospholipase A2 and increased expression of cyclooxygenase-2. Translocation of 5-lipoxygenase from the cytosol to the nucleus was not induced by ganglioside cross-linking. Cross-linking of GD1b derived gangliosides also resulted in the release of the newly synthesized mediators, interleukin-4, interleukin-6, and TNF-α. The effect of cross-linking the gangliosides on the MAP kinase pathway was then investigated. Cross-linking the gangliosides induced the phosphorylation of ERK1/2, JNK1/2, and p38 as well as activating both NFκB and NFAT in a Syk-dependent manner. Therefore, cross-linking the mast cell specific GD1b derived gangliosides results in the activation of signaling pathways that culminate with the release of newly formed and newly synthesized mediators. Edismauro Garcia Freitas Filho, Elaine Zayas Marcelino da Silva, Camila Ziliotto Zanotto, Constance Oliver, and Maria Célia Jamur Copyright © 2016 Edismauro Garcia Freitas Filho et al. All rights reserved. Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies Mon, 08 Aug 2016 11:39:16 +0000 Huntington’s disease (HD) is a neurodegenerative disorder characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline, and psychiatric disorders. Although the cause of HD is well described—HD is a genetic disorder caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin (HTT) on chromosome 4p16.3—the ultimate cause of neuronal death is still uncertain. Apart from impairment in systems for handling abnormal proteins, other metabolic pathways and mechanisms might contribute to neurodegeneration and progression of HD. Among these, inflammation seems to play a role in HD pathogenesis. The current review summarizes the available evidence about immune and/or inflammatory changes in HD. HD is associated with increased inflammatory mediators in both the central nervous system and periphery. Accordingly, there have been some attempts to slow HD progression targeting the immune system. Natalia P. Rocha, Fabiola M. Ribeiro, Erin Furr-Stimming, and Antonio L. Teixeira Copyright © 2016 Natalia P. Rocha et al. All rights reserved. Conjugated Bilirubin Differentially Regulates CD4+ T Effector Cells and T Regulatory Cell Function through Outside-In and Inside-Out Mechanisms: The Effects of HAV Cell Surface Receptor and Intracellular Signaling Thu, 04 Aug 2016 09:15:41 +0000 We recently reported an immune-modulatory role of conjugated bilirubin (CB) in hepatitis A virus (HAV) infection. During this infection the immune response relies on CD4+ T lymphocytes (TLs) and it may be affected by the interaction of HAV with its cellular receptor (HAVCR1/TIM-1) on T cell surface. How CB might affect T cell function during HAV infection remains to be elucidated. Herein, in vitro stimulation of CD4+ TLs from healthy donors with CB resulted in a decrease in the degree of intracellular tyrosine phosphorylation and an increase in the activity of T regulatory cells (Tregs) expressing HAVCR1/TIM-1. A comparison between CD4+ TLs from healthy donors and HAV-infected patients revealed changes in the TCR signaling pathway relative to changes in CB levels. The proportion of CD4+CD25+ TLs increased in patients with low CB serum levels and an increase in the percentage of Tregs expressing HAVCR1/TIM-1 was found in HAV-infected patients relative to controls. A low frequency of 157insMTTTVP insertion in the viral receptor gene HAVCR1/TIM-1 was found in patients and controls. Our data revealed that, during HAV infection, CB differentially regulates CD4+ TLs and Tregs functions by modulating intracellular pathways and by inducing changes in the proportion of Tregs expressing HAVCR1/TIM-1. Karla F. Corral-Jara, Jorge L. Trujillo-Ochoa, Mauricio Realpe, Arturo Panduro, Juan F. Gómez-Leyva, Yvonne Rosenstein, Alexis Jose-Abrego, Sonia Roman, and Nora A. Fierro Copyright © 2016 Karla F. Corral-Jara et al. All rights reserved. When Insult Is Added to Injury: Cross Talk between ILCs and Intestinal Epithelium in IBD Thu, 04 Aug 2016 09:07:15 +0000 Inflammatory bowel disease (IBD) is characterized by an impairment of the integrity of the mucosal epithelial barrier, which causes exacerbated inflammation of the intestine. The intestinal barrier is formed by different specialized epithelial cells, which separate the intestinal lumen from the lamina propria. In addition to its crucial role in protecting the body from invading pathogens, the intestinal epithelium contributes to intestinal homeostasis by its biochemical properties and communication to underlying immune cells. Innate lymphoid cells (ILCs) are a recently described population of lymphocytes that have been implicated in both mucosal homeostasis and inflammation. Recent findings indicate a critical feedback loop in which damaged epithelium activates these innate immune cells to restore epithelial barrier function. This review will focus on the signalling pathways between damaged epithelium and ILCs involved in repair of the epithelial barrier and tissue homeostasis and the relationship of these processes with the control of IBD. Esmé van der Gracht, Sonja Zahner, and Mitchell Kronenberg Copyright © 2016 Esmé van der Gracht et al. All rights reserved. Negative Impact of Hypoxia on Tryptophan 2,3-Dioxygenase Function Tue, 02 Aug 2016 12:05:55 +0000 Tryptophan is an essential amino acid for hosts and pathogens. The liver enzyme tryptophan 2,3-dioxygenase (TDO) provokes, by its ability to degrade tryptophan to N-formylkynurenine, the precursor of the immune-relevant kynurenines, direct and indirect antimicrobial and immunoregulatory states. Up to now these TDO-mediated broad-spectrum effector functions have never been observed under hypoxia in vitro, although physiologic oxygen concentrations in liver tissue are low, especially in case of infection. Here we analysed recombinant expressed human TDO and ex vivo murine TDO functions under different oxygen conditions and show that TDO-induced restrictions of clinically relevant pathogens (bacteria, parasites) and of T cell proliferation are abrogated under hypoxic conditions. We pinpointed the loss of TDO efficiency to the reduction of TDO activity, since cell survival and TDO protein levels were unaffected. In conclusion, the potent antimicrobial as well as immunoregulatory effects of TDO were substantially impaired under hypoxic conditions that pathophysiologically occur in vivo. This might be detrimental for the appropriate host immune response towards relevant pathogens. Frank Elbers, Claudia Woite, Valentina Antoni, Sara Stein, Hiroshi Funakoshi, Toshikazu Nakamura, Gereon Schares, Walter Däubener, and Silvia K. Eller Copyright © 2016 Frank Elbers et al. All rights reserved. Interplay between Oxidative Stress and Inflammation in Cardiometabolic Syndrome Tue, 02 Aug 2016 07:31:15 +0000 Aaron L. Sverdlov, Gemma A. Figtree, John D. Horowitz, and Doan T. M. Ngo Copyright © 2016 Aaron L. Sverdlov et al. All rights reserved. TLR2-Dependent Signaling for IL-15 Production Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes Mon, 01 Aug 2016 06:34:50 +0000 TLR2 signaling is related to colitis and involved in regulation of innate immunity in the intestinal tract, but the mechanisms remain unclear. The aim of this study is to investigate how TLR2 affects differentiation of intraepithelial lymphocytes (IELs) and regulates the susceptibility of colitis. IELs were isolated from the small intestine and colon of mice, respectively. The IEL phenotype, activation, and apoptosis were examined using flow cytometry and RT-PCR. IL-15 expression and IEL location were detected through immunohistochemistry. The experimental colitis was induced by administration of dextran sulfate sodium (DSS). We found that the numbers of CD8αα+, CD8αβ+, and TCRγδ+ IELs were significantly decreased in TLR2-deficient mice and the residual IELs displayed reduced activation and proliferation and increased apoptosis, accompanied with impaired IL-15 expression by intestinal epithelial cells (IECs). Further study showed that TLR2 signaling maintained the expression of IL-15 in IEC via NF-κB activation. Moreover, TLR2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis. Our results demonstrate that IECs contribute to the maintenance of IELs at least partly via TLR2-dependent IL-15 production, which provides a clue that may link IECs to innate immune protection of the host via IELs. Yuan Qiu, Aimin Pu, Hong Zheng, Minqiang Liu, Weigang Chen, Wensheng Wang, Weidong Xiao, and Hua Yang Copyright © 2016 Yuan Qiu et al. All rights reserved. Effect of Interferon-γ on the Basal and the TNFα-Stimulated Secretion of CXCL8 in Thyroid Cancer Cell Lines Bearing Either the RET/PTC Rearrangement Or the BRAF V600e Mutation Sun, 31 Jul 2016 17:04:47 +0000 CXCL8 displays several tumor-promoting effects. Targeting and/or lowering CXCL8 concentrations within the tumor microenvironment would produce a therapeutic benefit. Aim of this study was to test the effect of IFNγ on the basal and TNFα-stimulated secretion of CXCL8 in TCP-1 and BCPAP thyroid cancer cell lines (harboring RET/PTC rearrangement and BRAF V600e mutation, resp.). Cells were incubated with IFNγ (1, 10, 100, and 1000 U/mL) alone or in combination with TNF-α (10 ng/mL) for 24 hours. CXCL8 and CXCL10 concentrations were measured in the cell supernatants. IFNγ inhibited in a dose-dependent and significant manner both the basal (ANOVA F: 22.759; ) and the TNFα-stimulated (ANOVA F: 15.309; ) CXCL8 secretions in BCPAP but not in TPC-1 cells (NS). On the other hand, IFNγ and IFNγ + TNF-α induced a significant secretion of CXCL10 in both BCPAP () and TPC-1 () cells. Transwell migration assay showed that (i) CXCL8 increased cell migration in both TPC-1 and BCPAP cells; (ii) IFNγ significantly reduced the migration only of BCPAP cells; and (iii) CXCL8 reverted the effect of IFNγ. These results constitute the first demonstration that IFNγ inhibits CXCL8 secretion and in turn the migration of a BRAF V600e mutated thyroid cell line. Mario Rotondi, Francesca Coperchini, Oriana Awwad, Patrizia Pignatti, Christian A. Di Buduo, Vittorio Abbonante, Flavia Magri, Alessandra Balduini, and Luca Chiovato Copyright © 2016 Mario Rotondi et al. All rights reserved. Low-Dose Steroid Therapy Is Associated with Decreased IL-12 Production in PBMCs of Severe Septic Patients Sun, 31 Jul 2016 13:35:47 +0000 Background. Sepsis-induced immunosuppression may result in higher mortality rates in patients. Methods. We examined the relationship of cytokine responses from stimulated peripheral blood mononuclear cells (PBMCs) and monocyte human leukocyte antigen-DR (HLA-DR) expression (days 1 and 7) with low-dose steroid therapy in 29 septic patients. Patients were treated according to the guidelines. Thirty healthy controls were enrolled for validation. Results. Eighteen patients were prescribed low-dose steroids and 11 were not. Interleukin- (IL-) 12 responses in patients without low-dose steroid therapy on days 1 and 7 were higher than those with low-dose steroid therapy. Compared to day 1, IL-12 responses significantly increased on day 7 in patients without low-dose steroid therapy. After regression analysis, the change in the IL-12 response from day 7 to day 1 was found to be independently associated with the low-dose steroid therapy. There was no difference in monocyte HLA-DR expression between patients treated with and without low-dose steroid on day 1 or 7. No change in monocyte HLA-DR expression from day 7 to day 1 was observed in patients with or without low-dose steroid therapy. Conclusion. Decreased IL-12 response was associated with the low-dose steroid therapy in PBMCs of septic patients. Huang-Pin Wu, Chi-Chung Shih, Duen-Yau Chuang, and Tien-Hsing Chen Copyright © 2016 Huang-Pin Wu et al. All rights reserved. Pancreatic Acinar Cells Employ miRNAs as Mediators of Intercellular Communication to Participate in the Regulation of Pancreatitis-Associated Macrophage Activation Thu, 28 Jul 2016 13:01:57 +0000 Macrophage activation plays an important role in the inflammatory response in acute pancreatitis. In the present study, the activation of AR42J pancreatic acinar cells was induced by taurolithocholate treatment. The results showed that the culture medium from the activated AR42J cells significantly enhanced NFκB activation in the macrophages compared to that without taurolithocholate treatment. Additionally, the precipitates obtained from ultracentrifugation of the culture media that were rich in exosomes were markedly more potent in activating macrophages compared with the supernatant fraction lacking exosomes. The results indicated that the mediators carried by the exosomes played important roles in macrophage activation. Exosomal miRNAs were extracted and examined using microarrays. A total of 115 differentially expressed miRNAs were identified, and 30 showed upregulated expression, while 85 displayed downregulated expression. Target genes of the differentially expressed miRNAs were predicted using TargetScan, MiRanda, and PicTar software programs. The putative target genes were subjected to KEGG functional analysis. The functions of the target genes were primarily enriched in MAPK pathways. Specifically, the target genes regulated macrophage activation through the TRAF6-TAB2-TAK1-NIK/IKK-NFκB pathway. As the mediators of signal transduction, miRNAs and their predicted target mRNAs regulate every step in the MAPK pathway. Yong Zhao, Hao Wang, Ming Lu, Xin Qiao, Bei Sun, Weihui Zhang, and Dongbo Xue Copyright © 2016 Yong Zhao et al. All rights reserved. Association of Serum Adropin Concentrations with Diabetic Nephropathy Thu, 28 Jul 2016 10:15:42 +0000 Objective. Adropin is a newly identified regulatory protein encoded by the Enho gene and is critically involved in energy homeostasis and insulin sensitivity. This study aims to determine the correlation of serum adropin concentrations with diabetic nephropathy (DN). Methods. This study consisted of 245 patients with type 2 diabetes mellitus (T2DM) and 81 healthy subjects. Then T2DM patients were divided into normoalbuminuria, microalbuminuria, and macroalbuminuria subgroups based on urine albumin to creatinine ratio (ACR). Results. T2DM patients showed significantly lower serum adropin concentrations than those in the controls. T2DM patients with macroalbuminuria had significantly decreased serum adropin concentrations compared with the other three groups. In addition, T2DM patients with microalbuminuria showed lower serum adropin concentrations than those in patients with normoalbuminuria. Logistic regression analysis showed that serum adropin was correlated with decreased risk of developing T2DM and DN. Pearson correlation analysis indicated that serum adropin was negatively correlated with body mass index (BMI), blood urea nitrogen, creatinine, and ACR and positively correlated with glomerular filtration rate. Furthermore, multiple linear regression analysis showed that BMI and ACR were negatively correlated with serum adropin levels. Conclusion. Serum adropin concentrations are negatively associated with renal function. Adropin may be implicated in the pathogenesis of DN development. Wenchao Hu and Li Chen Copyright © 2016 Wenchao Hu and Li Chen. All rights reserved. The Plant-Derived Bauhinia bauhinioides Kallikrein Proteinase Inhibitor (rBbKI) Attenuates Elastase-Induced Emphysema in Mice Wed, 27 Jul 2016 08:25:06 +0000 Background. Elastase mediates important oxidative actions during the development of chronic obstructive pulmonary disease (COPD). However, few resources for the inhibition of elastase have been investigated. Our study evaluated the ability of the recombinant plant derived Bauhinia bauhinioides Kallikrein proteinase Inhibitor (rBbKI) to modulate elastase-induced pulmonary inflammation. Methods. C57Bl/6 mice were given intratracheal elastase (ELA group) or saline (SAL group) and were treated intraperitoneally with rBbKI (ELA-rBbKI and SAL-rBbKI groups). At day 28, the following analyses were performed: (I) lung mechanics, (II) exhaled nitric oxide (ENO), (III) bronchoalveolar lavage fluid (BALF), and (IV) lung immunohistochemical staining. Results. In addition to decreasing mechanical alterations and alveolar septum disruption, rBbKI reduced the number of cells in the BALF and decreased the cellular expression of TNF-α, MMP-9, MMP-12, TIMP-1, eNOS, and iNOS in airways and alveolar walls compared with the ELA group. rBbKI decreased the volume proportion of 8-iso-PGF2α, collagen, and elastic fibers in the airways and alveolar walls compared with the ELA group. A reduction in the number of MUC-5-positive cells in the airway walls was also observed. Conclusion. rBbKI reduced elastase-induced pulmonary inflammation and extracellular matrix remodeling. rBbKI may be a potential pharmacological tool for COPD treatment. Bruno Tadeu Martins-Olivera, Rafael Almeida-Reis, Osmar Aparecido Theodoro-Júnior, Leandro Vilela Oliva, Natalia Neto dos Santos Nunes, Clarice Rosa Olivo, Marlon Vilela de Brito, Carla Máximo Prado, Edna Aparecida Leick, Mílton de Arruda Martins, Maria Luiza Vilela Oliva, Renato Fraga Righetti, and Iolanda de Fátima Lopes Calvo Tibério Copyright © 2016 Bruno Tadeu Martins-Olivera et al. All rights reserved.