Inflammatory Cytokines IL-1α Research Articles

MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract

MERS-CoV, a highly pathogenic virus in humans, is associated with high morbidity and case fatality. Inflammatory responses have a significant impact on MERS-CoV pathogenesis and disease outcome. However, CD4+ T-cell induced immune responses during acute MERS-CoV infection are barely detectable, with potent inhibition of effector T cells and downregulation of antigen presentation. The local pulmonary immune response, particularly the Th1 and Th2-related immune response during acute severe MERS-CoV infection is not fully understood. In this study, we offer the first insights into the pulmonary gene expression profile of Th1 and Th2-related cytokines/chemokines (Th1 & Th2 responses) during acute MERS-CoV infection using RT2 Profiler PCR Arrays. We also quantified the expression level of primary inflammatory cytokines/chemokines. Our results showed a downregulation of Th2, inadequate (partial) Th1 immune response and high expression levels of inflammatory cytokines IL-1α and IL-1β and the neutrophil chemoattractant chemokine IL-8 (CXCL8) in the lower respiratory tract of MERS-CoV infected patients. Moreover, we identified a high viral load in all included patients. We also observed a correlation between inflammatory cytokines, Th1, and Th2 downregulation and the case fatality rate. Th1 and Th2 response downregulation, high expression of inflammatory cytokines, and high viral load may contribute to lung inflammation, severe infection, the evolution of pneumonia and ARDS, and a higher case fatality rate. Further study of the molecular mechanisms underlying the Th1 and Th2 regulatory pathways will be vital for active vaccine development and the identification of novel therapeutic strategies.

12/15-lipoxygenase supports inflammatory cytokine production and PMN recruitment during invasive aspergillosis

Abstract Eicosanoids are a family of inflammatory lipid mediators produced via the metabolism of arachidonic acid by a network of biosynthetic enzymes. We and others have recently shown that pathways within this network, specifically the cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) pathways, participate in induction of protective immune responses during invasive aspergillosis (IA). Based on the high degree of cooperation and interconnection within the eicosanoid network, we hypothesized that a third core enzyme, 12/15-lipoxygenase (12/15-LOX), also may support innate antifungal responses. We report here that mice deficient in the gene encoding 12/15-LOX, Alox15, exhibit decreased survival and increased fungal burden in a model of IA. These defects were associated with decreased PMN numbers in the lung and decreased levels of PMN chemokines (CXCL1, CXCL2, CCL3) in Alox15−/− mice, while fungal killing by PMNs in vitro was unaffected. Alox15−/− mice produced lower levels of the inflammatory cytokines IL-17A, IL-22, IL-1α and IL-6 during infection. iNKT cells, which we have reported to be a major cell source of IL-22 during IA, were present in decreased numbers in Alox15−/− mice. This reduction was associated with lower levels of IL-7, a cytokine we have recently shown to be required for optimal numbers of iNKT cells during IA. Decreased IL-22 levels were further associated with decreased levels of IL-23. Together, these data indicate that 12/15-LOX is a critical player in induction of multiple aspects of the innate immune response to A. fumigatus.

A comparative study of skin irritation caused by novel bis-quaternary ammonium compounds and commonly used antiseptics by using cell culture methods

New bis-quaternary ammonium compounds (bis-QACs) 3-(3-hydroxy-2-(hydroxymethyl)-2-{[(1-dodecylpyridinium-3-yl)oxy]methyl}propoxy)-1-dodecylpyridinium dibromide (3HHDMP-12) and 3,3′-[1,4-phenylenebis(oxy)]bis(1-dodecylpyridinium) dibromide (3PHBO-12) were compared with commonly-used antiseptics such as benzalkonium chloride (BAC), octenidine dihydrochloride (OCT), chlorhexidine digluconate (CHG) and polyhexamethylene biguanide (PHMB), to evaluate their potential to cause skin irritation. The cytotoxicity of these compounds in various cultured cells, as well as their effect on the expression of inflammatory cytokine genes such as IL-1α were evaluated.The cytotoxic effect of these bis-QACs on several types of human-derived cells was lower than that of common quaternary ammonium compounds (BAC and OCT), although the bis-QACs showed higher cytotoxicity than the biguanide-based compounds (CHG and PHMB). In addition, IL-1α mRNA expression was more strongly induced by BAC and OCT than by the new bis-QACs, at concentrations below the IC50 obtained in normal human epidermal keratinocytes. Furthermore, even at the actual therapeutic concentration, the new bis-QACs did not alter inflammatory cytokine mRNA expression or IL-1α secretion as demonstrated using the reconstructed human epidermis model LabCyte EPI-MODEL.The results suggested that the potential of 3PHBO-12 and 3HHDMP-12 to induce skin irritation is comparable to or less than that of existing antiseptics, and these bis-QACs may be useful antiseptics with few side effects.

Correlations of SOX9 expression with serum IGF1 and inflammatory cytokines IL-1α and IL-6 in skin lesions of patients with acne.

To study the correlations of sex determining region Y-box 9 (SOX9) expression with serum type-1 insulin-like growth factor (IGF-1), interleukin-1α (IL-1α), and interleukin-6 (IL-6) in skin lesion tissues of patients with acne. Six patients with acne who were treated for the first time in our outpatient clinic from June 2017 to July 2017 were selected as observation group, and 6 normal subjects were selected as control group. The expression of SOX9 was detected by immunohistochemistry. The protein expressions of IGF-1, IL-1α, and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA). SOX9 was detected by quantitative polymerase chain reaction (qPCR). Compared with that in control group, the expression of SOX9 in observation group was significantly increased (p < 0.05). Compared with those in control group, the expressions of IGF-1, IL-1α and IL-6 in observation group were significantly increased (p < 0.05). Compared with that in control group, the mRNA expression of SOX9 in observation group was significantly increased (p < 0.05). SOX9 was positively correlated with IGF-1, IL-1α and IL-6. The expressions of SOX9, IGF-1, IL-1α, and IL-6 in skin lesion tissues of patients with acne are increased, and SOX9 is positively correlated with IGF-1, IL-1α, and IL-6 and can be used as a target for the treatment of acne inflammation.

AB019. 2’-fucosyllactose: a common human milk oligosaccharide with uncommon effects

: Human milk (HM) is a complex matrix containing numerous unique components compared to infant formula. One such group of components, human milk oligosaccharides (HMO), is abundant in HM and only exceeded in amount by lipid and lactose. Of the various HMOs, the most predominant HMO in HM is commonly 2’-fucosyllactose (2’FL). The increased availability of selected synthesized HMOs in recent years has allowed for the opportunity to study the preclinical and clinical effects of some of these compelling oligosaccharides. This presentation will review the roles of 2’FL as well as reviewing the emerging science as it relates to the young infant. Preclinical work supports 2’FL as a prebiotic, immune modulator, and a potential anti-nociceptive by regulating colonic contractions in mice. Additionally, more recent emerging preclinical research in rodents supports that 2’FL enhances cognition via the gut-brain axis. Learning and memory skills in both young and adult rodents that are dependent on the integrity of the vagus nerve appear to be impacted by 2’FL feeding. Recent clinical research has revealed that infants fed infant formula with 2’FL during the first 4 months of life exhibited innate immune responses closer to those of HM-fed infants than did infants fed formula without 2’FL. This included decreased levels of circulating innate inflammatory cytokines IL-1ra, IL-1α, IL-1β, IL-6, and TNF-α in HM- and 2’FL formula-fed infants. Additionally, unlike those from infants fed formula without 2’FL, ex vivo peripheral blood mononuclear cell cultures from HM- and 2’FL-fed infants had decreased concentrations of innate inflammatory cytokines IL-1ra, IL-1β, IL-6, TNF-α, and IFN-γ at 48 hours post respiratory syncytial virus infection. New preclinical and clinical work continues to reveal new functions of 2’FL. (Research funded by Abbott Nutrition, Abbott Laboratories).

In vitro examination of an oleosome-based sun protection product on the influence of UVB-induced inflammation markers in human epidermal skin equivalent tissue model

In vitro human epidermal skin equivalent tissues (MatTek EpiDerm™) were employed to examine the influence of UVB radiation on various established inflammation markers in the presence of topically applied sunscreens. MatTek EpiDerm™ tissues were treated with 2.0mg/cm2 of an Experimental oleosome-based SPF 30 product or a commercial SPF 30 beach product. Tissues were irradiated with 300mJ/cm2 of UVB radiation. Inflammatory cytokines IL-1α, IL-6 and IL-8 as well as arachidonic acid cascade marker PGE2 were examined via ELISA-based antibody detection. Untreated tissues irradiated with 300mJ/cm2 of UVB radiation showed statistically significant upregulation of IL-1α, IL-6 and IL-8 as well as PGE2. Application of both the experimental oleosome-based SPF 30 formulation and the commercial SPF 30 formulation demonstrated an ability to prevent the upregulation of all four markers when applied prior to irradiation. The experimental oleosome-based SPF 30 product contained approximately 80% less sunscreen actives than the commercial formulation. This study demonstrates that in vitro reconstructed human tissues can be used to study the influences of sun screen actives in the presence of UVB radiation. The results support previously reported clinical results that demonstrated that oleosome-based sun care formulations can function with high protection effects with significantly less sun care actives.

Biocompatibility and Osteogenic/Calcification Potential of Casein Phosphopeptide-amorphous Calcium Phosphate Fluoride

IntroductionCasein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and CPP-ACP with fluoride (CPP-ACFP) have been shown to provide bioavailable ions to promote mineralization. Hence, the aim of this study was to evaluate the materials’ biocompatibility and osteogenic/calcification potential for endodontic applications. MethodsHuman and mouse osteoblast-like and fibroblast-like cell lines were incubated with 0.05%–3.0% w/v CPP-ACP and CPP-ACFP, and toxicity, proliferation, alkaline phosphatase, interleukin (IL)-1α, and IL-6 production, collagen type I, osteocalcin, and osteopontin production, and mineralization/calcification were determined. ResultsCPP-ACP and CPP-ACFP were non-toxic and had no significant effect on proliferation or production of the inflammatory cytokine IL-1α. Alkaline phosphatase activity of the osteoblast-like cells was significantly increased (P < .05) by CPP-ACP and CPP-ACFP, as was the production of the osteotropic cytokine IL-6, the formation of calcium mineral deposits, and the secretion of mineralization-related proteins (collagen type I and osteocalcin). ConclusionsCPP-ACP and CPP-ACFP are biocompatible and have the potential to induce osteoblastic differentiation and mineralization. Potential applications include apexification, perforation repair, vital pulp therapy, and regenerative endodontic procedures.

Topical administration of Esculetin as a potential therapy for experimental dry eye syndrome

PurposeIn this study, we investigated the therapeutic effects of topical Esculetin for dry eye rabbits through the ocular tests, inflammatory factor levels and specific phosphorylated protein expressions of ERK1/2 singnal pathway.Patients and methodsThirty-two healthy adult male New Zealand white rabbits were chosen for the study. DES models were established after removing of the main lacrimal gland, Harderian gland and nictitating membrane in the left eyes and randomly divided into group DES control, group CsA, group Esculetin and group Esculetin combined with CsA (C&E), meanwhile the right eyes served as group Normal control. Schirmer's I tests, fluorescein scores, goblet cell densities, inflammatory cytokines IL-1α,IL-1β,TNF-αlevels were observed by slit-lamp microscope, conjunctival impression cytology and ELISA essay at week 0, 1, 2, 4, 8. Phosphorylated-ERK1/2 expressions were detected in Western blot analysis at week 8.ResultsAfter induction of DES, aqueous tear production and goblet cell density were decreased, FL score was much higher in group DES control throughout the study (P<0.05). Both topical Esculetin and Esculetin combing CsA increased the SIT values (10±1 mm, 14±3 mm, P<0.05) and goblet cell densities (77±12/HP, 92±12/HP, P<0.05), decreased FL scores (7.48±0.33, 5.09±0.24, P<0.05) at week 8. Alternations of IL-1α,IL-1β,TNF-αlevels had similar trend. In Western blot analysis, downregulations of p-ERK1/2 were observed in therapy groups when compared with group DES control and the most decreasing was found in group C&E (P<0.05).ConclusionTopical Esculetin improved DES symptoms, downregulated the inflammatory cytokine expressions, suppressed the ERK1/2 pathway and enhanced the therapeutic effect of CsA.

Inflammatory Adipokines Decrease Expression of Two High Molecular Weight Isoforms of Tropomyosin Similar to the Change in Type 2 Diabetic Patients.

Cardiovascular disease and cancer are increased in Type 2 diabetes. TPM1 and TPM4 genes encode proteins associated with cardiovascular and neoplastic disease. High (HMW) and low (LMW) molecular weight isoforms from TPM1 and TPM4 are altered in several cancer cells and the 3'UTR of TPM1 mRNA is tumour suppressive. Leukocytes influence cardiovascular and neoplastic disease by immunosurveillance for cancer and by chronic inflammation in Type 2 diabetes and cardiovascular disease. The aim was to determine changes in expression of isoforms from TPM1 and TPM4 genes in leukocytes from Type 2 diabetic patients and to use the leukocyte cell line THP1 to identify possible mediators of changes in the patients. Gene expression was determined by RT-qPCR. In diabetes, expression of HMW isoforms from TPM1 were markedly decreased (0.55 v 1.00; p = 0.019) but HMW isoforms from TPM4 were not significantly different (0.76 v 1.00; p = 0.205). Within individual variance in expression of HMW isoforms was very high. The change in expression in HMW isoforms from TPM1 and TPM4 was replicated in THP1 cells treated with 1 ng/ml TNFα (0.10 and 0.12 v 1.00 respectively) or 10 ng/ml IL-1α (0.17 and 0.14 v 1.00 respectively). Increased insulin or glucose concentrations had no substantial effects on TPM1 or TPM4 expression. Decreased TPM1 mRNA resulted in decreases in HMW protein levels. Expression of HMW isoforms from TPM1 is decreased in Type 2 diabetes. This is probably due to increased levels of inflammatory cytokines TNFα and IL-1α in Type 2 diabetes. Lower levels of TPM1 mRNA reduce tumour suppression and could contribute to increased cancer risk in Type 2 diabetes. Decreased HMW tropomyosin isoforms are associated with cancer. Decreased HMW isoforms give rise to cells that are more plastic, motile, invasive and prone to dedifferentiation resulting in leukocytes that are more invasive but less functionally effective.

Modeling IL-1 induced degradation of articular cartilage

In this study, we develop a computational model to simulate the in vitro biochemical degradation of articular cartilage explants sourced from the femoropatellar grooves of bovine calves. Cartilage explants were incubated in culture medium with and without the inflammatory cytokine IL-1α. The spatio-temporal evolution of the cartilage explant's extracellular matrix components is modelled. Key variables in the model include chondrocytes, aggrecan, collagen, aggrecanase, collagenase and IL-1α. The model is first calibrated for aggrecan homeostasis of cartilage in vivo, then for data on (explant) controls, and finally for data on the IL-1α driven proteolysis of aggrecan and collagen over a 4-week period. The model was found to fit the experimental data best when: (i) chondrocytes continue to synthesize aggrecan during the cytokine challenge, (ii) a one to two day delay is introduced between the addition of IL-1α to the culture medium and subsequent aggrecanolysis, (iii) collagen degradation does not commence until the total concentration of aggrecan (i.e. both intact and degraded aggrecan) at any specific location within the explant becomes ≤1.5 mg/ml and (iv) degraded aggrecan formed due to the IL-1α induced proteolysis of intact aggrecan protects the collagen network while collagen degrades in a two-step process which, together, significantly modulate the collagen network degradation. Under simulated in vivo conditions, the model predicts increased aggrecan turnover rates in the presence of synovial IL-1α, consistent with experimental observations. Such models may help to infer the course of events in vivo following traumatic joint injury, and may also prove useful in quantitatively evaluating the efficiency of various therapeutic molecules that could be employed to avoid or modify the course of cartilage disease states.

Inflammatory Cytokine Il-1α Up-Regulates Piezo1 and Hyper-Sensitizes Chondrocytes to Compression

In diarthrodial joints, chondrocyte mechanotransduction play a critical role in the maintenance of cartilage and in the pathogenesis of osteoarthritis (OA). The mechanistic understanding of chondrocyte mechanotransduction both in health and disease is essential for the rational prevention and treatment of joint diseases. We recently identified that injurious mechanical stress is transduced by the mechano-sensitive ion channels Piezo1 and Piezo2 in chondrocytes; blocking Piezo1/2 protected chondrocytes from injurious mechanical stress, suggesting a possible therapeutic benefit of this approach in cartilage injury or OA. Yet, little is known about how the OA joint environment may influence Piezo1/2-mediated mechanotransduction. We hypothesize that mechanotransduction of chondrocytes is altered by OA-related inflammatory stress, and that Piezo1/2 gene expression and function is altered in the context of OA.Here, we present new data in support of increased expression of Piezo1 in chondrocytes under inflammatory conditions, associated with sensitization to mechanical stimulation. We found that in the presence of pathophysiologically relevant concentrations of IL-1α, (1) the basal Ca2+ concentration of articular chondrocytes was increased (∼90nM), (2) mechanically activated Ca2+ influx was increased (∼50 nM by a compression force of 300nN), (3) Piezo1 mRNA levels increased (∼2 fold). These findings suggest sensitization of chondrocytes to mechanical cues via enhanced expression of Piezo1 channels. Also IL-1α treatment resulted in increased cell strain (∼4%) at the same compressive load and attenuated cortical actin labeling, indicative of increased actin destabilization, whereas β-tubulin remained unaffected. These data indicate that IL-1α-exposed chondrocytes (and potentially their membranes) can deform more readily, thereby elevating gating probabilities of mechanosensitive ion channels.Our study shows that the OA-associated inflammatory cytokine IL-1α alters chondrocyte mechanotransduction, suggesting that chondrocytes’ mechanical hypersensitivity is due to upregulated Piezo1 mRNA expression caused by IL-1α-signaling.

Effects of perinatal exposure to nonylphenol on delivery outcomes of pregnant rats and inflammatory hepatic injury in newborn rats.

The current study aimed to investigate the effects of perinatal exposure to nonylphenol (NP) on delivery outcome of pregnant rats and subsequent inflammatory hepatic injury in newborn rats. The pregnant rats were divided into 2 groups: control group (corn oil) and NP exposure group. Thirty-four pregnant rats were administered NP or corn oil by gavage from the sixth day of pregnancy to 21 days postpartum, with blood samples collected at 12 and 21 days of pregnancy and 60 days after delivery. The NP concentration was measured by HPLC, with chemiluminescence used for detection of estrogen and progesterone levels. Maternal delivery parameters were also observed. Liver and blood of the newborn rats were collected and subjected to automatic biochemical detection of liver function and blood lipid analyzer (immunoturbidimetry), and ultrastructural observation of the hepatic microstructure, with the TNF-α and IL-1β hepatic tissue levels evaluated by immunohistochemistry. Compared with the control group, the pregnant and postpartum serum NP and estradiol levels of the mother rats in the NP group were significantly increased, together with lowered progesterone level, increased number of threatened abortion and dystocia, and fewer newborn rats and lower litter weight. Serum and hepatic NP levels of the newborn rats measured 60 days after birth were significantly higher than those of the control group, as well as lower testosterone levels and increased estradiol levels. When observed under electron microscope, the hepatocyte nuclei of the control group were large and round, with evenly distributed chromatin. The chromatin of hepatocytes in the NP group presented deep staining of the nuclei, significant lipid decrease in the cytoplasm, and the majority of cells bonded with lysate. The results of immunohistochemistry showed that there was almost no TNF-α or IL-1β expression in the hepatocytes of the control group, while the number of TNF-α-, PCNA-, and IL-1β-positive cells in the NP group was increased, with higher integral optical density than the control group. Compared to the control group, the serum levels of alanine aminotransferase, aspartate aminotransferase, triglyceride and low-density lipoprotein in the newborn rats of the NP group were significantly increased. There was no significant difference in the serum level of high-density lipoprotein or cholesterol between the groups. Perinatal exposure to NP can interfere with the in vivo estrogen and progesterone levels of pregnant rats, resulting in threatened abortion, dystocia and other adverse delivery outcomes. High liver and serum NP levels of the newborn rats led to alteration of liver tissue structure and function. The NP-induced hepatotoxicity is probably mediated by inflammatory cytokines TNF-α and IL-1α.

Aminoguanidine cream ameliorates skin tissue microenvironment in diabetic rats.

IntroductionThe aim of the study was to explore the effect of aminoguanidine cream on the skin tissue microenvironment in diabetic rats.Material and methodsA total of 51 healthy male Sprague Dawley (SD) rats were randomly divided into three groups: the diabetes group (n = 18), the aminoguanidine group (n = 18) and the control group (n = 15). Rats in the diabetes group and aminoguanidine group were injected with 65 mg/kg streptozotocin to induce the diabetes model, and in the control group with citrate buffer. After successful induction of diabetes, the back hair of all rats was stripped by barium sulfide, and the aminoguanidine group was treated with aminoguanidine cream using disinfected cotton swabs twice every day for 40 days, while the diabetes and control groups were treated with the cream matrix. The pathological changes of skin were observed by HE staining, while the content of inflammatory cytokines (TNF-α, IL-8, ICAM and IL-1α) and the antioxidant indexes (T-AOC, GSH-PX, MPO MDA H2O2) were examined using commercial kits.ResultsAfter 40 days of treatment, the diabetes group manifested tissue lesions, whereas the aminoguanidine group seemed normal. Compared with the diabetes group, the content of inflammatory cytokines TNF-α, IL-8, ICAM and IL-1α was dramatically lower in the aminoguanidine group. T-AOC in all groups underwent dramatic changes and returned to normal finally. The activities of GSH-PX and MPO and content of H2O2 in the diabetes group were all higher than those in the aminoguanidine group.ConclusionsAminoguanidine may have a good systemic effect on alleviating the pathological changes of skin tissue in diabetic rats, which may be attributed to the regulation of GSH-PX, TNF-α, IL-8, ICAM and IL-1α.

Sustained Inhibition of Proliferative Response After Transient FGF Stimulation Is Mediated by Interleukin 1 Signaling.

Transient FGF stimulation of various cell types results in FGF memory--a sustained blockage of efficient proliferative response to FGF and other growth factors. FGF memory establishment requires HDAC activity, indicating its epigenetic character. FGF treatment stimulates proinflammatory NFκB signaling, which is also critical for FGF memory formation. The search for FGF-induced mediators of FGF memory revealed that FGF stimulates HDAC-dependent expression of the inflammatory cytokine IL1α. Similarly to FGF, transient cell treatment with recombinant IL1α inhibits the proliferative response to further FGF and EGF stimulation, but does not prevent FGF receptor-mediated signaling. Interestingly, like cells pretreated with FGF1, cells pretreated with IL1α exhibit enhanced restructuring of actin cytoskeleton and increased migration in response to FGF stimulation. IRAP, a specific inhibitor of IL 1 receptor, and a neutralizing anti-IL1α antibody prevent the formation of FGF memory and rescue an efficient proliferative response to FGF restimulation. A similar effect results following treatment with the anti-inflammatory agents aspirin and dexamethasone. Thus, FGF memory is mediated by proinflammatory IL1 signaling. It may play a role in the limitation of proliferative response to tissue damage and prevention of wound-induced hyperplasia.

Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies.

The inflammatory cytokines IL-1α and IL-1β orchestrate local and systemic inflammatory responses underlying a broad spectrum of diseases. Three agents for reducing IL-1 activities are currently available. Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist. Anakinra binds to the IL-1 receptor and prevents the activity of IL-1α and IL-1β. The soluble decoy receptor rilonacept and the neutralizing mAb canakinumab block IL-1β. A mAb directed against the IL-1 receptor and a neutralizing anti-human IL-1α are in clinical trials. The availability of therapies specifically targeting IL-1 unveiled the pathological role of IL-1-mediated inflammation in a broadening list of diseases. Conditions effectively treated with agents blocking IL-1 range from classic rheumatic diseases, such as RA and gout, to autoinflammatory syndromes, such as systemic JIA and FMF. However, IL-1 antagonism is also effective against highly prevalent inflammatory diseases, namely cardiovascular diseases and type 2 diabetes, conditions that are frequently encountered as co-morbidities in patients with rheumatic diseases. Thereby, IL-1 inhibition has the potential to lift the burden of disease for patients with rheumatic conditions, but also to provide clinical benefits beyond the efficacy on osteoarticular manifestations.

IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs.

Intravital visualization of thrombopoiesis revealed that formation of proplatelets, which are cytoplasmic protrusions in bone marrow megakaryocytes (MKs), is dominant in the steady state. However, it was unclear whether this is the only path to platelet biogenesis. We have identified an alternative MK rupture, which entails rapid cytoplasmic fragmentation and release of much larger numbers of platelets, primarily into blood vessels, which is morphologically and temporally different than typical FasL-induced apoptosis. Serum levels of the inflammatory cytokine IL-1α were acutely elevated after platelet loss or administration of an inflammatory stimulus to mice, whereas the MK-regulator thrombopoietin (TPO) was not elevated. Moreover, IL-1α administration rapidly induced MK rupture-dependent thrombopoiesis and increased platelet counts. IL-1α-IL-1R1 signaling activated caspase-3, which reduced plasma membrane stability and appeared to inhibit regulated tubulin expression and proplatelet formation, and ultimately led to MK rupture. Collectively, it appears the balance between TPO and IL-1α determines the MK cellular programming for thrombopoiesis in response to acute and chronic platelet needs.

Translation inhibition by bacterial pathogens: links to inflammation (INM1P.428)

Abstract Legionella pneumophila is an intracellular bacterial pathogen that is the cause of a severe pneumonia in humans called Legionnaires’ Disease. L. pneumophila infects alveolar macrophages and its virulence requires a type IV secretion system (T4SS) that injects bacterial effector proteins into the host cytosol. Macrophages distinguish infection with T4SS+ (virulent) and T4SS- (avirulent) bacteria, and mount several distinct immune responses to virulent bacteria. Virulent L. pneumophila induces a block in host protein synthesis that is partially induced by 7 bacterial effectors that directly block host translation. L. pneumophila infection also induces the inflammatory cytokine IL-1α. We link translation inhibition to the production of IL-1α, and show that IL-1α signaling, through the interleukin-1 receptor, protects the host during L. pneumophila infection. We show that translation inhibition leads to a sustained production of Il1a transcript and we suggest that this overcomes the block in translation and allows for preferential production of inflammatory cytokines in infected macrophages. To gain insight into the L. pneumophila induced block in host translation, we used ribosome profiling and RNAseq of L. pneumophila infected macrophages to analyze global and mRNA-specific translation rates. Our data suggest that translation inhibition induced by pathogenic infection may be an important pathway that induces inflammation and protects animals from multiple bacterial pathogens.

Association of the invasion ability of Porphyromonas gingivalis with the severity of periodontitis

Porphyromonas gingivalis is one of the well-characterized periodontal pathogens involved in periodontitis. The invasive and proteolytic activities of P. gingivalis clinical isolates have been shown to be associated with heterogenic virulence, as determined in a mouse abscess model. The aims of the present study were to identify a P. gingivalis strain with a low virulence among clinical isolates, based on its invasive ability and cytokine proteolytic activities, and to explore the preferential degradation of a certain cytokine by P. gingivalis. P. gingivalis ATCC 33277, W50, and 10 clinical isolates were used. After incubating bacteria with IL-4, IL-6, IL-10, IL-17A, TNFα, IFNγ, and IL-1α, the amounts of remaining cytokines were determined by ELISA. Invasion ability was measured by a flow cytometric invasion assay. There was inter-strain variability both in the cytokine proteolytic activities and invasion ability. In addition, differential degradation of cytokines by P. gingivalis was observed: while IFNγ and IL-17A were almost completely degraded, inflammatory cytokines TNFα and IL-1α were less susceptible to degradation. Interestingly, the invasion index, but not cytokine proteolytic activities, of P. gingivalis had strong positive correlations with clinical parameters of subjects who harbored the isolates. Therefore, the invasive ability of P. gingivalis is an important virulence factor, and the bacterial invasion step may be a good target for new therapeutics of periodontitis.

Oral Mucosal Tolerance Versus Systemic Immune Response to Salmonella typhi Antigen

It was demonstrated that the oral vaccine application of Salmonella typhi antigen can activate low antibody agglutinin titer (mean:40±0) comparing with high agglutination titer induced by Intramuscular administration of Salmonella typhi antigen (mean 560.0 ± 51.64) as well as anti-Salmonella typhi IgG ELIZA shows high mean index value(mean = 0.6957±0.10) comparing with the low index value induced by oral rout were (mean= 0.028±0.014) while anti Salmonella typhi IgM ELIZA test show mean index value = 0.6339±0.0385 comparing with low IgM index value (mean= 0.1560±0.070) induced by oral rout (Rsquared 0.7457, t test 3.3. The pro –inflammatory cytokines IL-1α was high in intramuscular rout 217.089±39.78 than its concentration with in oral administrated group (100.4±12.09), IL-12 was about the same concentration both in oral rout and intramuscular rout subsequently (23.607 and 23.17) p value 0.01, R squared (0.3958).However the immune responses were not absolutely absent in the oral administrated group, this reflect the fact that there is a selectivity in taking oral antigens from digestive mucosal surfaces but this immune feature and selectivity theme may vary from antigen to another. In conclusion the recent and ongoing expansion of a new information about the mucosal and systemic immune responses lend a promise to provide the tools needed to exploit the full potential and development of both mucosal and intramuscular vaccines.

Hyponeurotrophinemia in Serum of Women with Polycystic Ovary Syndrome as a Low Grade Chronic Inflammation

Introduction: This study aimed to discuss about neuroimmune-pathophysiology of polycystic ovary syndrome (PCOS). Nerve growth factor (NGF) as modulator of neuro-endocrine-immune (NEI) system plays a critical role in tissue survival and homeostasis maintenance. It is a strong marker for sympathetic nerve activity. Women with PCO have enhanced ovarian NGF production. Over the past few decades, PCOS has been discussed as a low grade chronic inflammatory disease. In this study, we investigated the neuromodulator role of serum NGF and inflammatory cytokines (IL-1α, β, 17A and TNF-α) in women with PCOS. Material and Methods: 171 patients were investigated in two groups: study (n = 85 PCO) and control (n = 86). Serum levels of NGF-α and interleukins IL-1α, IL-1β, IL-17A and TNFα were determined in both groups by ELISA kit. Results: Data of this study showed that the level of NGF-α and IL-17A in serum of PCO women were lower than control group (p α, IL-1β were higher than control group in PCO women (p α, IL-1β. Reduction of IL-17A and NGF in serum of PCO patients might be under the direct influence of the hyperactivity of sympathetic nervous system (SNS).