Secretion Of Pro-inflammatory Mediators Research Articles

Exploring the wound healing, anti-inflammatory, anti-pathogenic and proteomic effects of lactic acid bacteria on keratinocytes

The topical application of lactic acid bacteria (LAB) is recognized as a useful approach to improve skin health. This work aims to characterize by a multidisciplinary approach, the wound healing, anti-inflammatory, anti-pathogens and proteomic effects of six LAB lysates, belonging to the genus Lactobacillus. Our results demonstrated that the lysates of tested LAB stimulated the proliferation of keratinocytes, and that L. plantarum SGL 07 and L. salivarius SGL 19 accelerated the re-epithelization by inducing keratinocyte migration. The bacterial lysates also reduced the secretion of specific pro-inflammatory mediators from keratinocytes. Furthermore, viable L. salivarius SGL 19 and L. fermentum SGL 10 had anti-pathogenic effects against S. aureus and S. pyogenes, while L. brevis SGL 12 and L. paracasei SGL 04 inhibited S. aureus and S. pyogenes, respectively. The tested lactobacilli lysates also induced specific proteome modulation of the exposed keratinocytes, involving dysregulation of proteins (such as interleukin enhancer-binding factor 2 and ATP-dependent RNA helicase) and pathways (such as cytokine, NF-kB, Hedgehog, and RUNX signaling) associated with their specific wound healing and anti-inflammatory effects. This study indicates the different potential of selected lactobacilli, suggesting that they may be successfully used in the future together with conventional therapies to bring relief from skin disorders.

Oxidative stress-mediated epidermal growth factor receptor activation regulates PM2.5-induced over-secretion of pro-inflammatory mediators from human bronchial epithelial cells

BackgroundExposure to PM2.5 has been associated with increased morbidity and mortality of lung diseases although the underlying mechanisms have not been fully uncovered. Airway inflammation is a critical event in the pathogenesis of lung diseases. This study aimed to examine the role of oxidative stress and epidermal growth factor receptor (EGFR) in PM2.5-induced pro-inflammatory response in a human bronchial epithelial cell line, BEAS-2B. MethodsBEAS-2B cells were exposed to 0, 20, 50, 100 and 150 μg/ml of PM2.5. Secretion of pro-inflammatory mediators including interleukin-6 (IL-6), IL-8 and IL-1β was determined using enzyme linked immunosorbent assay. Levels of intracellular reactive oxygen species (ROS) were determined using flow cytometry. Phosphorylation of the EGFR was examined with immunoblotting. ResultsPM2.5 exposure increased the secretion of IL-6, IL-8, and IL-1β in a concentration-dependent fashion. Moreover, exposure to PM2.5 elevated intracellular levels of ROS, and phosphorylation of the EGFR (Y1068). Pretreatment of BEAS-2B cells with either an antioxidant or a specific EGFR inhibitor significantly reduced PM2.5-induced IL-6, IL-8 and IL-1β secretion, implying that both oxidative stress and EGFR activation were involved in PM2.5-induced pro-inflammatory response. Furthermore, pre-treatment of BEAS-2B cells with an antioxidant significantly blunted PM2.5-induced EGFR activation, suggesting that oxidative stress was required for PM2.5-induced EGFR activation. ConclusionPM2.5 exposure induces pro-inflammatory response in human bronchial epithelial cells through oxidative stress-mediated EGFR activation.

Toll-like receptors in the pathophysiology of obesity

Obesity is a complex and relevant global medical and social problem. The adipose tissue is not only a place of deposition of energy substrates but also a source of secretion of pro-inflammatory and anti-inflammatory mediators involved in the development of the chronic latent systemic inflammatory process in the organism with obesity. The metabolic signal in obesity contributes to the polarization of macrophages in the M1 direction and triggers the Th1 immune response, causing the development of adipose tissue inflammation. A chronic inflammatory condition plays a key role in the pathophysiology of obesity-induced insulin resistance. Toll-like receptors (TLRs) may be a possible pathophysiological link in the development of insulin resistance in inflammation. At the same time, inflammation-induced lipolysis is necessary for the release of energy resources during the development of the infectious process. Thus, low-grade inflammation is important to protect against adipocyte dysfunction. These results suggest that pro-inflammatory signaling is not exclusively pathogenic in obesity. In this regard, the study of inflammatory signaling pathways involved in the modulation of chronic inflammation of adipose tissue is particularly relevant. This review summarizes current views on the structure, function of TLRs and their involvement in the pathogenesis of chronic inflammation in obesity. The possibility of using TLRs as a therapeutic target in this pathology is discussed. Obviously, further study of inflammatory signaling pathways involving TLRs initiating the development of chronic inflammation of adipose tissue will allow the development of new and effective therapeutic strategies for obesity and its metabolic complications.

Expression of virulence factors and pro-inflammatory cytokines by Candida species associated with Vulvovaginal Candidiasis in Eastern Nigeria

Abstract Introduction Candida albicans (CA) is a major cause of vulvovaginal candidiasis (VVC). Adherence to vaginal epithelial cells (VECs) is considered the first step in Candida colonization and eventual invasion of the vaginal mucosa; extracellular hydrolytic enzymes play important role in the invasion of the host. Transition from colonizing yeast cells to tissue-invading hyphae results in secretion of pro-inflammatory mediators, such as IFN-γ, IL-1β, and IL-17. Our earlier reports suggested increasing involvement of non-albicans Candida species (NAC) in VVC, in our locality. We, therefore, saw the need to compare local isolates of CA and NAC for virulence potentials and production of key inflammatory cytokines. Materials and Methods Isolates of CA and NAC were investigated for proteinase, phospolipase, and haemolytic activity, as well as ability to adhere to vaginal epithelial cells (VECs) of women of Child-bearing age. The isolates were also inoculated (intra-vaginally) into mice, and assayed for IFN-γ, IL-1β, and IL-17. Results Production of phospholipase, proteinase, and haemolysis, by the isolates, were as follows: (CA = 57%, 91%, and 100%; NAC = 10%, 83%, and 78%, respectively). Mean adherence to VECs was: NAC (2.90+3.40); CA (2.81+2.0). Comparable levels of cytokines were generated by CA and NAC in vaginal wash and serum, although NAC produced slightly more IL-17 than CA in day 14. Conclusion Based on the results, it could be concluded that the increasing prevalence of NAC in VVC could possibly be as a result of increasing immuno-compromising states of women in our locality, rather than etiological factors.

Structural Similarity with Cholesterol Reveals Crucial Insights into Mechanisms Sustaining the Immunomodulatory Activity of the Mycotoxin Alternariol.

The proliferation of molds in domestic environments can lead to uncontrolled continuous exposure to mycotoxins. Even if not immediately symptomatic, this may result in chronic effects, such as, for instance, immunosuppression or allergenic promotion. Alternariol (AOH) is one of the most abundant mycotoxins produced by Alternaria alternata fungi, proliferating among others in fridges, as well as in humid walls. AOH was previously reported to have immunomodulatory potential. However, molecular mechanisms sustaining this effect remained elusive. In differentiated THP-1 macrophages, AOH hardly altered the secretion of pro-inflammatory mediators when co-incubated with lipopolysaccharide (LPS), opening up the possibility that the immunosuppressive potential of the toxin could be related to an alteration of a downstream pro-inflammatory signaling cascade. Intriguingly, the mycotoxin affected the membrane fluidity in macrophages and it synergistically reacted with the cholesterol binding agent MβCD. In silico modelling revealed the potential of the mycotoxin to intercalate in cholesterol-rich membrane domains, like caveolae, and immunofluorescence showed the modified interplay of caveolin-1 with Toll-like Receptor (TLR) 4. In conclusion, we identified the structural similarity with cholesterol as one of the key determinants of the immunomodulatory potential of AOH.

Resolution of Inflammation in Neurodegenerative Diseases: The Role of Resolvins.

Acute inflammation has been described as a reactive dynamic process, promoted by the secretion of proinflammatory mediators, including lipid molecules like leukotrienes and prostaglandins, and counterbalanced by proresolving mediators including omega-3 polyunsaturated fatty-acid- (PUFA-) derived molecules. The switch from the initiation to the resolution phase of acute inflammatory response is crucial for tissue homeostasis, whereas the failure to resolve early inflammation by specialized proresolving mediators leads to chronic inflammation and tissue damage. Among PUFA-derived proresolving mediators, different eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derivatives have been described, namely, resolvins (resolution phase interaction products), which exert their anti-inflammatory and immune-regulatory activities through specific G-protein-coupled receptors. In recent years, compelling evidence has shown that impairment of resolution of inflammation is a crucial pathogenic hallmark in different neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. This review summarizes current knowledge on the role of resolvins in resolution of inflammation and highlights available evidence showing the neuroprotective potential of EPA- and DHA-derived resolvins (E-series and D-series resolvins, respectively) in neurodegenerative diseases.

Puerarin inhibits inflammation and oxidative stress in dextran sulfate sodium-induced colitis mice model

Ulcerative colitis (UC) is an inflammatory bowel disease accompanied by abdominal pain, diarrhea, and rectal bleeding. The aim of this study was to investigate whether puerarin, one of the main components of the root of Pueraria lobata, exerts anti-inflammatory and anti-oxidative effects against UC. To examine the anti-inflammatory and anti-oxidative effects of puerarin against colitis, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis. Administration of puerarin alleviated colon shortening, pathological damage to the colon, and myeloperoxidase (MPO) activity. Puerarin significantly inhibited inflammation through the down-regulation of nuclear factor-κB (NF-κB) and the secretion of pro-inflammatory mediators. Moreover, puerarin showed anti-oxidative effects through the regulation of the expression of the NF-E2 p45-related factor 2 (Nrf2) pathway and antioxidant enzymes. Puerarin inhibited intestinal epithelial barrier dysfunction by increasing the expression of tight junction proteins. These results suggest that puerarin has anti-inflammatory and anti-oxidative effects in the mouse model of colitis.

Sesamum indicum (sesame) enhances NK anti-cancer activity, modulates Th1/Th2 balance, and suppresses macrophage inflammatory response

Objective: To evaluate the potential immunomodulatory effects of an aqueous extract of Sesamum indicum seeds with regard to splenocyte proliferation, Th1/Th2 balance, macrophage function, and the cytotoxic activity of natural killer (NK) cells. Methods: Splenocyte proliferation was measured by [3H]- thymidine incorporation. Griess assay was performed to evaluate the production of nitric oxide by macrophages. The levels of cytokines secreted by splenocytes and macrophages were measured by ELISA. JAM assay was performed to examine the cytotoxic activity of NK cells against YAC-1 tumor cells. Results: Sesamum indicum significantly enhanced splenocyte proliferation in a dose-dependent manner. Sesamum indicum also increased and suppressed the secretion of Th1 and Th2 cytokines, respectively, by splenocytes. The secretion of key pro-inflammatory mediators (IL-6, TNFα, and nitric oxide) by primary macrophages was significantly inhibited by Sesamum indicum. Moreover, Sesamum indicum increased the cytotoxic activity of NK cells against YAC-1 tumor cells. Conclusions: Sesamum indicum shows potent immunomodulatory, anti-inflammatory, and anti-cancer effects. Constituents of Sesamum indicum may be used as effective therapeutic agents in regulating immune reactions implicated in various infectious and non- infectious conditions including cancer.

IL-17 Induced Stromal Cell\u2013Derived Factor-1 and Profibrotic Factor in Keloid-Derived Skin Fibroblasts via the STAT3 Pathway

The pathogenesis of keloids has not been elucidated, and the disease is thought to be caused by abnormal secretion of proinflammatory mediators and irregular responses to other inflammatory signals mediated by keloid fibroblasts (KFs). In this study, we investigated whether a local increase in interleukin IL-17 in keloid tissues stimulates the production of stromal cell–derived factor-1 (SDF-1) in KFs causing further recruitment of IL-17-producing T helper 17 (Th17) cells, which subsequently creates a positive feedback loop. Histological assessment was performed and the change in the expression of IL-17, IL-1β, IL-6, and TNF-α which of fibrosis and inflammation associated markers was examined. In addition, fibroblasts were treated with IL-17 in the presence or absence of STAT3 inhibitor STA-21; SDF-1 levels and fibrosis genes were measured. Our results showed that fibrotic reaction and expression of proinflammatory cytokines including IL-17 were most prominent in the growing margin (perilesional area) of keloid tissue and Th17 cells significantly infiltrated the perilesional area. In addition, IL-17 upregulated the expression of SDF-1, collagen, and α-SMA in KFs. Finally, STA-21 decreased SDF-1α expression and the expression of fibrosis genes in KFs even after IL-17 stimulation. Our study demonstrated that a local increase in IL-17 in keloid tissues stimulates the production of SDF-1 in KFs causing further recruitment of IL-17-producing T helper 17 (Th17) cells, which subsequently creates a positive feedback loop. These findings suggest that STAT3 inhibition can be used to treat keloid scars by reversing the vicious cycle between Th17 cells and KFs.

Platelets in Inflammation and Resolution

Platelets have long been known for their role in hemostasis. In this, platelet adhesion and activation leads to the formation of a firm thrombus and thus the sealing of a damaged blood vessel. More recently, inflammatory modes of function have been attributed to these non-nuclei-containing cellular fragments. Interaction with leukocytes, secretion of proinflammatory mediators, and migratory behavior are some of the recent discoveries. Nonetheless, platelets also have anti-inflammatory potential by regulating macrophage functions, regulatory T cells, and secretion of proresolving mediators. This review summarizes current knowledge of platelet functions with a special focus on inflammation and resolution of inflammation.

P4142PI3-kinase delta protects against atherosclerosis progression by governing regulatory T-cell biology

Abstract Introduction and purpose Atherosclerosis is a chronic inflammatory disease of arteries and represents the main underlying cause of death worldwide. Macrophages are major drivers of atherosclerosis by ingestion of lipoproteins, foam cell formation, and secretion of pro-inflammatory mediators. Although macrophages outnumber other leukocytes in atherosclerotic plaques, T and B lymphocytes can shape the course of disease by promoting or mitigating inflammatory responses. Leukocytes highly express the phosphoinositide 3-kinase isoform delta (PI3Kd), exerting a key role in the regulation of immune responses including the activation, proliferation, differentiation, and effector function of lymphocytes. Since macrophages and lymphocytes are all major effectors of atherosclerosis, we aimed to understand the role of PI3Kd in these leukocytes during atherogenesis. Methods and results To investigate the role of haematopoietic PI3Kd in atherosclerosis, bone marrow from PI3Kd−/− or PI3Kd+/+ mice was transplanted into LDLR−/− mice. After 6 weeks of feeding on an atherogenic diet, PI3Kd−/− recipient LDLR−/− mice displayed significantly impaired CD4+ and CD8+ T-cell numbers, CD4+ T-cell activation, CD4+ effector T cells, and proatherogenic CD4+ T helper (Th) 1 responses in para-aortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the net effect of PI3Kd deficiency was a substantial increase of aortic inflammation and atherosclerosis in LDLR−/− mice. Moreover, haematopoietic PI3Kd deficiency augmented macrophage accumulation in atherosclerotic plaques of LDLR−/− mice, whereas major macrophage functions including foam cell formation, efferocytosis, and cytokine secretion were unaffected by PI3Kd inactivation in these phagocytes. However, haematopoietic PI3Kd deficiency led to depletion of atheroprotective B-1 cells and reduction of proatherogenic B-2 cells in LDLR−/− mice. Moreover, haematopoietic PI3Kd deficiency caused a significant reduction of regulatory CD4+ T cells (Tregs) in plaques, para-aortic lymph nodes, and spleen of LDLR−/− mice. Furthermore, PI3Kd−/− Tregs exhibited reduced secretion of anti-inflammatory cytokines IL-10 and TGF-b as well as impaired suppression of CD4+ T-cell proliferation. Consequently, adoptive transfer of PI3Kd+/+ Tregs fully constrains the atherosclerotic burden in PI3Kd−/− transplanted LDLR−/− mice without affecting B cell numbers. Conclusions We demonstrate that PI3Kd plays a crucial role in B lymphocytes, Th1 cells, and Tregs during atherogenesis. Lack of PI3Kd signalling in atheroprotective Treg responses outplays its impact on proatherogenic Th1 responses, thus leading to aggravated atherosclerosis. Hence, PI3Kd is a key regulator of Treg biology and thereby protects against atherosclerosis progression. Acknowledgement/Funding Center for Molecular Medicine Cologne (CMMC) and the Marga and Walter Boll-Stiftung

Inhibitory effects of diallyl sulfide on the activation of Kupffer cell in lipopolysaccharide/d-galactosamine-induced acute liver injury in mice

Abstract Diallyl sulfide (DAS) is an effective bioactive organosulfur compound extracted from garlic. This study aimed to explore whether the protective effect of DAS on lipopolysaccharide (LPS)/ d -galactosamine ( d -GalN) induced acute liver injury was associated with the regulation of Kupffer cell (KC) activation. The results indicated that DAS administration protected mice from LPS/D-GalN-induced histopathological damage and serum aminotransferase elevation and also showed more pronounced beneficial effects than GdCl3 administration. The F4/80+ or CD11b+ KC immunohistochemistry results showed that DAS administration suppressed LPS/D-GalN-induced KC activation. DAS administration also suppressed LPS/D-GalN-triggered production of TNF-α, IL-1β, MCP-1 and NO in the liver or serum, which was in line with the mRNA expression of TNF-α, IL-1β, IL-6, MCP-1 and iNOS in the liver. Taken together, these findings reveal that the protective effects of DAS on LPS/D-GalN-induced acute liver injury may be achieved by inhibiting the activation of KC, thereby suppressing the secretion of various proinflammatory mediators.

Lactobacillus pentosus S-PT84 prevents LPS-induced low-grade chronic inflammation in a C57BL/6J mouse model

Abstract Chronic exposure to low-dose of endotoxin triggers a pronounced inflammatory responses impairing gut physical barrier and resulting in microbiota dysbiosis. In this study, we investigated the anti-inflammatory activity of dietary heat killed (HK) Lactobacillus pentosus S-PT84 in a lipopolysaccharides (LPS)-induced low-grade chronic inflammation C57BL/6J mouse model. The results showed that the deficient expression of tight junction proteins (ZO-1, Cldn 3 and JAMA) and mucin 2 were restored by HK L. pentosus S-PT84. Subsequently, HK L. pentosus S-PT84 attenuated the secretion of pro-inflammatory mediators (TNF-α and MCP-1) and the decreased levels of adiponectin with a reduction in macrophage infiltration in white adipose tissue (WAT). Moreover, the dysfunctional metabolic activity observed in WAT was significantly inhibited through upregulation of PPAR-γ and IRS-1 expression. The dysbiosis in gut microbiota were prevented by HK L. pentosus S-PT84. These findings suggest that HK L. pentosus S-PT84 exerts protective effects on intestinal mucosal integrity and an early risk for progression into metabolic disorders.

1020 - NEW INSIGHTS INTO INFLAMMASOME SIGNALLING AND FUNCTION DURING INFLAMMATION

Inflammasomes are signalling hubs that assemble in response to cell stress or microbial infection, and provide an activation platform for the zymogen protease, caspase-1. Upon activation, caspase-1 triggers the maturation and secretion of potent pro-inflammatory mediators (interleukin-1beta and -18) and induces cell lysis, culminating in the activation of the immune system and antimicrobial defence. Inflammasome signalling can, however, also drive pathology in a range of human auto-inflammatory, inflammatory, metabolic and neurodegenerative diseases. Here we reveal the mechanisms by which inflammasomes signal, and how a small molecule inflammasome inhibitor can silence pathological inflammasome signalling for therapeutic management of disease.

Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools.

Chronic kidney disease (CKD) is an increasing health burden (affecting approximately 13.4% of the population). Currently, no curative treatment options are available and treatment is focused on limiting the disease progression. The accumulation of senescent cells has been implicated in the development of kidney fibrosis by limiting tissue rejuvenation and through the secretion of pro-fibrotic and pro-inflammatory mediators termed as the senescence-associated secretory phenotype. The clearance of senescent cells in aging models results in improved kidney function, which shows promise for the options of targeting senescent cells in CKD. There are several approaches for the development of “senotherapies”, the most rigorous of which is the elimination of senescent cells by the so-called senolytic drugs either newly developed or repurposed for off-target effects in terms of selectively inducing apoptosis in senescent cells. Several chemotherapeutics and checkpoint inhibitors currently used in daily oncological practice show senolytic properties. However, the applicability of such senolytic compounds for the treatment of renal diseases has hardly been investigated. A serious concern is that systemic side effects will limit the use of senolytics for kidney fibrosis. Specifically targeting senescent cells and/or targeted drug delivery to the kidney might circumvent these side effects. In this review, we discuss the connection between CKD and senescence, the pharmacological options for targeting senescent cells, and the means to specifically target the kidney.

Comprehensive Kinetic Survey of Intestinal, Extra-Intestinal and Systemic Sequelae of Murine Ileitis Following Peroral Low-Dose Toxoplasma gondii Infection.

We have recently shown that following peroral low-dose Toxoplasma gondii infection susceptible mice develop subacute ileitis within 10 days. Data regarding long-term intestinal and extra-intestinal sequelae of infection are scarce, however. We therefore challenged conventional C57BL/6 mice with one cyst of T. gondii ME49 strain by gavage and performed a comprehensive immunopathological survey 10, 36, and 57 days later. As early as 10 days post-infection, mice were suffering from subacute ileitis as indicated by mild-to-moderate histopathological changes of the ileal mucosa. Furthermore, numbers of apoptotic and proliferating/regenerating epithelial cells as well as of T and B lymphocytes in the mucosa and lamina propria of the ileum were highest at day 10 post-infection, but declined thereafter, and were accompanied by enhanced pro-inflammatory mediator secretion in ileum, colon and mesenteric lymph nodes that was most pronounced during the early phase of infection. In addition, subacute ileitis was accompanied by distinct shifts in the commensal gut microbiota composition in the small intestines. Remarkably, immunopathological sequelae of T. gondii infection were not restricted to the intestines, but could also be observed in extra-intestinal tissues including the liver, kidneys, lungs, heart and strikingly, in systemic compartments that were most prominent at day 10 post-infection. We conclude that the here provided long-term kinetic survey of immunopathological sequalae following peroral low-dose T. gondii infection provides valuable corner stones for a better understanding of the complex interactions within the triangle relationship of (parasitic) pathogens, the host immunity and the commensal gut microbiota during intestinal inflammation. The low-dose T. gondii infection model may be applied as valuable gut inflammation model in future pre-clinical studies in order to test potential treatment options for intestinal inflammatory conditions in humans.

Guggulipid ameliorates adjuvant-induced arthritis and liver oxidative damage by suppressing inflammatory and oxidative stress mediators

BackgroundArthritis is a common degenerative joint disease characterized by deterioration of articular cartilage, subchondral bone, and associated with immobility, pain and inflammation. The incessant action of reactive oxygen species (ROS) during progressive arthritis causes severe oxidative damage to vital organs and circulatory system. PurposeIn this study we investigated the ability of guggulipid (GL), a lipid rich extract from the gum resin of the plant Commiphora whighitii to suppress the progressive arthritis and associated liver oxidative stress both in vivo and in vitro. Study design/MethodsThe anti-arthritic ability of GL was demonstrated in vitro using IL-1β stimulated bovine nasal cartilage model and in vivo Freund's complete adjuvant-induced arthritic rat model. Collagen/proteoglycan degradation and pro-inflammatory mediators were monitored in the harvested culture medium of nasal cartilage by estimating the levels of matrix metalloproteinases (MMPs), hydroxy proline, glycosaminoglycans and inflammatory mediators. Further, anti-arthritic ability of GL was evaluated in vivo by measuring enzymatic and non-enzymatic mediators of cartilage degradation, inflammation and oxidative stress markers. ResultsGL significantly inhibited the IL-1β stimulated cartilage degradation in vitro by mitigating the MMPs activity, collagen degradation and secretion of pro-inflammatory mediators. Further, GL significantly reduced the adjuvant-induced paw swelling and body weight loss in vivo. GL remarkably reduced the MMPs and hyaluronidases activities in serum and bone homogenate along with altered hematological parameters. GL also mitigated the elevated bone resorbing enzymes cathepsins, exoglycosidases and phosphatases. Additionally, GL effectively mitigated ROS and oxidative stress-mediators recuperating the altered serum/liver oxidative stress and liver damage incurred during arthritic progression. ConclusionIn summary, the study clearly demonstrates the protective efficacy of GL against arthritis and its associated oxidative stress, particularly, liver oxidative damage. Hence, GL could be a potential alternative and complementary medicine to treat inflammatory joint diseases.

Receptor-destroying enzyme (RDE) from Vibrio cholerae modulates IgE activity and reduces the initiation of anaphylaxis

IgE plays a key role in allergies by binding to allergens and then sensitizing mast cells through the Fc receptor, resulting in the secretion of proinflammatory mediators. Therefore, IgE is a major target for managing allergies. Previous studies have reported that oligomannose on IgE can be a potential target to inhibit allergic responses. However, enzymes that can modulate IgE activity are not yet known. Here, we found that the commercial receptor-destroying enzyme (RDE) (II) from Vibrio cholerae culture fluid specifically modulates IgE, but not IgG, and prevents the initiation of anaphylaxis. RDE (II)-treated IgE cannot access its binding site on bone marrow-derived mast cells, resulting in reduced release of histamine and cytokines. We also noted that RDE (II)-treated IgE could not induce passive cutaneous anaphylaxis in mouse ears. Taken together, we concluded that RDE (II) modulates the IgE structure and renders it unable to mediate allergic responses. To reveal the mechanism by which RDE (II) interferes with IgE activity, we performed lectin microarray analysis to unravel the relationship between IgE modulation and glycosylation. We observed that RDE (II) treatment significantly reduced the binding of IgE to Lycopersicon esculentum lectin, which recognizes poly-N-acetylglucosamine and poly-N-acetyllactosamine. These results suggest that RDE (II) specifically modulates branched glycans on IgE, thereby interfering with its ability to induce allergic responses. Our findings may provide a basis for the development of drugs to inhibit IgE activity in allergies.

Dietary Rice Bran Oil and γ‐Oryzanol Attenuates Toll Like Receptor‐mediated IκBα Phosphorylation, NF‐κB p65 Activation and Matrix Metallo Protease‐9 Expression in Peritoneal Macrophages from Rats Fed Partially Hydrogenated Vegetable Fat and thereby Exhibit Anti‐Inflammatory Activity

In spite of warning issued by regulatory agencies all over the world, South Asian countries are continuing to use Partially Hydrogenated Vegetable Fat (PHVF) in many food products. PHVF contains trans fatty acid known as elaidic acid which is pro‐inflammatory. NF‐κB p65 and Matrix Metallo Proteases‐9 (MMP‐9) play an important role in promoting inflammation. Dietary Rice bran oil (RBO) and γ‐ORY reduce the secretion of inflammatory mediators from macrophages as compared to those obtained from rats fed diet containing PHVF and thereby exhibit anti‐inflammatory activity. The present study was focused on specific role of RBO and γ‐ORY on the phosphorylation of IκBα, subsequent activation of NF‐κB p65 and secretion of Matrix Metallo Proteases (MMP‐9) a mechanism by which RBO and γ‐ORY may be exhibiting their anti‐inflammatory activity. Male wistar rats were fed AIN‐93 diet for 60 days. The diet was supplemented with one of the following fat/oil at 10wt%level: PHVF, RBO‐N (unfrationated oil), RBO‐MCR (Minor Constituents Removed oil), RBO‐MCR+Unsaponifiable Matter from Rice Bran Oil added back to RBO‐MCR (UM RBO‐MCR), RBO‐MCR+ γ‐ORY(700mg/kg diet), PHVF+RBO‐N (5.0+5.0wt%), PHVF+ γ‐ORY (700mg/kg diet). The macrophages from rats fed diet containing PHVF showed increased phosphorylation of IκB, translocation of NF‐κB p65, enhanced secretion of MMP‐9 indicating pro‐inflammatory nature of dietary PHVF. Diet containing RBO‐N, RBO‐MCR, UM RBO‐MCR and RBO‐MCR+ γ‐ORY significantly reduced phosphorylation of IκB, translocation of NF‐κB p65 and expression of MMP‐9 in macrophages all of which were enhanced when PHVF diets were fed to rats. Thus RBO and its components like γ‐ORY exhibit anti‐inflammatory activity by modulating expression of NF‐κB p65 which ultimately results in decreased secretion of pro‐inflammatory mediators by macrophages.Support or Funding InformationDepartment of Biotechnology, IndiaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Brevenal, a Marine Natural Product, is Anti-Inflammatory and an Immunomodulator of Macrophage and Lung Epithelial Cells.

Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are some of the leading causes of illness and fatalities worldwide. The search for novel treatments led to the exploration of marine natural products as drug candidates to combat the debilitating effects of mucus accumulation and chronic inflammation. Previous research showed that an alga-derived compound, brevenal, could attenuate the effects of inflammatory agents, but the mechanisms by which it exerted its effects remained unclear. We investigated the effects of brevenal on lipopolysaccharide (LPS) induced cytokine/chemokine production from murine macrophages and human lung epithelial cells. It was found that brevenal reduces proinflammatory mediator secretion while preserving anti-inflammatory secretion from these cells. Furthermore, we found that brevenal does not alter cell surface Toll-like receptor 4 (TLR4) expression, thereby maintaining the cells’ ability to respond to bacterial infection. However, brevenal does alter macrophage activation states, as demonstrated by reduced expression of both M1 and M2 phenotype markers, indicating this putative anti-inflammatory drug shifts innate immune cells to a less active state. Such a mechanism of action would be ideal for reducing inflammation in the lung, especially with patients suffering from chronic respiratory diseases, where inflammation can be lethal.