Inducible Protein-10 Research Articles

Immunomodulatory effects of cigarette smoke condensate in mouse macrophage cell line.

Increasing evidence has demonstrated that the secretion of cytokines may be associated with cigarette smoke–induced immunomodulatory effects, but a comprehensive analysis of the cytokine profile for cigarette smoke condensate (CSC) exposure is lacking. The aims of this study were to (1) examine the release of 20 cytokines induced by CSC from 12 brands of cigarettes in macrophages cells (Ana-1) and (2) to investigate the general characteristics of the immunomodulatory effects of CSC. Luminex technology was used to simultaneously determine the levels of 20 cytokines (interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), keratinocyte-derived Chemokine (KC), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), induced protein 10 (IP-10), tumor necrosis factor α (TNF-α), vascular endothelial growth factor (VEGF), monkine inducible by γ interferon (MIG), and fibroblast growth factor (FGF)-basic) in the supernatants from Ana-1 cells treated with the CSC. The results showed that the release of eight cytokines was altered (IL-5, IL-6, IL-12, TNF-α, VEGF, IP-10, MCP-1, and MIP-1α) compared with the control. These cytokines fall into two major subtypes: proinflammatory cytokines, including IL-5, IL-6, IL-12, TNF-α, and VEGF, and chemokines, including IP-10, MCP-1, and MIP-1α. Compared with control, the remaining 12 cytokines were not significantly affected by CSC from the 12 brands of cigarettes. As a general characteristic, CSC exerts potently suppressive immunomodulatory effects on cytokine production of Ana-1 cells. Proinflammatory cytokines and chemokines may account for or contribute to the immunosuppressive properties of CSC.

Active HCV infection is associated with increased circulating levels of interferon-gamma (IFN-γ)-inducible protein-10 (IP-10), soluble CD163 and inflammatory monocytes regardless of liver fibrosis and HIV coinfection

Interferon-gamma (IFN-γ)-inducible protein-10 (IP-10), soluble (s) CD163 and sCD14 play an important role in the pathogenesis of HCV and HIV infection and are involved in inflammation and liver fibrosis. The aim of the present study was to evaluate at a single time point, plasma soluble biomarkers and inflammatory monocytes subsets in different groups of subjects: (i) HIV monoinfected patients on suppressive ART; (ii) HIV/HCV coinfected patients on ART, with undetectable HIV viremia (including either subjects who had active HCV replication or those who cleared HCV); (iii) HCV monoinfected individual with active viral replication. Hundred and twenty-nine plasma samples were analyzed including HCV and HIV monoinfected patients, HIV/HCV coinfected patients, with active HCV infection (AHI) or with HCV viral clearance (VHC) and healthy donors (HD). Levels of IP-10, sCD163 and sCD14 were measured by ELISA. Absolute cell counts of monocyte subpopulations were enumerated in whole blood by using flow cytometric analyses. IP-10 and sCD163 plasma levels were higher in HCV monoinfected and in AHI coinfected pts compared to HIV monoinfected and HD, whereas sCD14 levels were higher only in HIV monoinfected patients. Considering the degree of fibrosis, sCD163 and sCD14 levels positively correlated with kPa values (as assessed by fibroscan) and FIB-4 in HCV monoinfected group. On the other hand, IP-10 did not correlate with the fibrosis stage and it was found increased also in patients with low fibrosis. Moreover, we found an increase of the inflammatory NCM subset, in non-cirrhotic HCV subjects, while no alterations were observed in HIV, AHI and VHC. Our study suggests a scenario in which active HCV infection is associated with a strong pro-inflammatory state, even in the initial stage of liver fibrosis, regardless the presence of HIV coinfection, thus underlying the need of an early anti-HCV treatment.

Comparison of 0.3% Hypotonic and Isotonic Sodium Hyaluronate Eye Drops in the Treatment of Experimental Dry Eye

ABSTRACTPurpose: To compare the efficacy of 0.3% hypotonic and isotonic sodium hyaluronate (SH) eye drops in the treatment of experimental dry eye.Methods: Experimental dry eye was established in female C57BL/6 mice by subcutaneous scopolamine injection and an air draft. The mice were divided into three groups (n = 15): control, preservative-free 0.3% isotonic SH, and preservative-free 0.3% hypotonic SH. The tear volume, tear film break-up time, and corneal fluorescein staining scores were measured 5 and 10 days after treatment. After conjunctival tissues were excised at 10 days, the levels of interleukin (IL)-6, IL-17, interferon (IFN)-γ, and IFN-γ inducible protein-10 were determined using the multiplex immunobead assay. In addition, PAS staining and flow cytometry were performed to evaluate the counts of conjunctival goblet cells and CD4+ IFN-γ+ T cells.Results: Mice treated with 0.3% hypotonic SH showed a significant decrease in corneal staining scores (P = 0.04) and the levels of IL-6 (16.7 ± 1.4 pg/mL, P = 0.02) and IFN-γ (46.5 ± 11.5 pg/mL, P = 0.02) compared to mice treated with 0.3% isotonic SH (IL-6; 32.5 ± 8.8 pg/mL, IFN-γ; 92.0 ± 16.0 pg/mL) at day 10. Although no significant difference in CD4+ IFN-γ+ T cell numbers was observed, goblet cell counts were higher in the hyopotonic SH group than in the isotonic SH group (P = 0.02).Conclusions: When compared to 0.3% isotonic SH eye drops, 0.3% hypotonic SH eye drops can be more effective by improving corneal staining scores, decreasing inflammatory molecules, and increasing goblet cell counts for experimental dry eye. These data suggest that hypotonic artificial tears may be useful as an adjunctive treatment for inflammatory dry eye.

Cytokine profiles of amyopathic dermatomyositis with interstitial lung diseases treated with mycophenolate

A 59‐year‐old Japanese man diagnosed with interstitial lung disease associated with amyopathic dermatomyositis with anti‐melanoma differentiation‐associated gene 5 (MDA‐5) antibodies was treated with intravenous methyl prednisolone (PSL) 1000 mg, oral PSL 1 mg/kg, and oral cyclosporin 200 mg daily. His respiratory condition worsened after treatment with two times of intravenous cyclophosphamide and another steroid pulse therapy as well as PSL and cyclosporin. Addition of mycophenolate mofetil (MMF), 1.5 g daily improved PaO2/FiO2 (PF) ratio of the patient from 294 to 360 at 4 weeks and 416 at 15 weeks after addition of MMF. We measured cytokine concentration in preserved serum taken at 11 and 7 weeks before addition of MMF and at 4, 11, and 15 weeks after MMF administration. Of the 28 cytokines evaluated, the concentrations of fibroblast growth factors‐2 (FGF‐2), chemokine (C‐X3‐C motif) ligand 1 (CX3CL1), interleukin (IL)‐1ra, IL‐17A, inducible protein 10 (IP‐10), and monocyte chemotactic protein‐1 (MCP‐1) decreased after addition of MMF. These results suggest that MMF may be beneficial to patients with interstitial lung disease by modification of the cytokine/growth factor protein expression.

Aqueous cytokine and growth factor levels indicate response to ranibizumab for diabetic macular oedema

Background/AimsTo investigate the relations between aqueous humour levels of cytokines/growth factors and treatment response to intravitreal ranibizumab (IVR) for diabetic macular oedema (DME)MethodsSixty-eight eyes of 68 patients with treatment-naïve centre-involved...

The association of urinary interferon-gamma inducible protein-10 (IP10/CXCL10) levels with kidney allograft rejection.

Interferon-gamma inducible protein-10 (IP-10/CXCL10) is a chemokine involved in the alloimmune response against kidney allograft. We aimed to investigate the association of urinary CXCL10 protein levels with rejection in renal transplant patients. A total of 273 urine samples from (biopsy-proven) rejection and non-rejection patients and controls were included in this study. CXCL10 levels were analyzed for association with rejection. The data showed statistically significant differences in the CXCL10 levels between rejection vs. non-rejection (p < 0.001). Among the rejection groups, statistically significant differences for CXCL10 levels were found between ACR vs. NAD (p < 0.001), ACR vs. BLR (p = 0.019) and AVR vs. NAD (p = 0.009). Receiver Operating Characteristic (ROC) curve analysis of CXCL10 showed an area under the curve (AUC) of 0.74 with 72% sensitivity and 71% specificity at 27.5pg/ml between rejection and non-rejection group. Kaplan-Meier curve analysis among different levels of CXCL10 showed a better rejection-free graft survival in patients with <100pg/ml when compared to >200pg/ml (38 ± 6 vs. 12 ± 1.0 weeks; log-rank p < 0.001) and 100-200pg/ml (38 ± 6 vs. 22 ± 9 weeks; log-rank p = 0.442) concentration. The results indicate significantly increased levels of CXCL10 protein in the urine at the time of allograft rejection. This association of urinary CXCL10 protein levels with rejection could provide an additional tool for the non-invasive monitoring of allograft rejection.

The mechanism of human β-defensin 3 in MRSA-induced infection of implant drug-resistant bacteria biofilm in the mouse tibial bone marrow.

The mechanism of human β-defensin 3 (HBD-3) in methicillin-resistant Staphylococcus aureus (MRSA-induced infection of implant drug-resistant bacteria biofilm in the mouse tibial bone marrow was studied. Healthy adult male Sprague-Dawley rats with average weight of 230 g were selected to construct the infection model of MRSA-induced implant drug-resistant bacteria biofilm in the mouse left tibial bone marrow. The drugs were intraperitoneally injected after 24 h medullary cavity infection, and the experimental groups included the model group, HBD-3 group, and vancomycin group (20 rats in each group). The model group was injected with 10 ml saline, HBD-3 group was injected with 10 ml of 8 µg/ml (1 MIC) and vancomycin group was injected with 10 ml of 0.5 µg/ml (1 MIC), five animals in each group were sacrificed on the 1, 7, 14 and 21 days, respectively. Observation was carried out on whether there was swelling and purulent secretion on the local wound; 1 ml venous sinus blood of eye socket was collected for blood routine examination and blood culture, and the laser scanning confocal microscopy was used to observe the morphology of the biofilm on the implant surface and the number of viable bacteria. Immunohistochemical staining was adopted to test the expression of nuclear factor-κB (NF-κB) and toll-like receptor 4 (TLR-4), and ELISA method was used to test interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), IL-1α and interferon-γ (INF-γ)-inducible protein-10 (IP-10) expression levels. There was no death due to infection in the HBD-3 group or vancomycin group, 1 case with significant wound swelling was found, respectively, in each group, but there was no purulent secretion. The percentage of the total white blood cells and neutrophil granulocytes as well as the biofilm morphology and the number of viable bacteria in the model group was gradually increased with time, while those in the HBD-3 group and vancomycin group were decreased with time. The comparative difference among groups was statistically significant (P<0.05); those in the HBD-3 group and vancomycin group at each time-point was decreased significantly compared with the model group, and the difference among groups was statistically significant (P<0.05), but in terms of the comparison between the HBD-3 group and vancomycin group, the difference was not significantly different (P>0.05). The NF-κB and TLR-4 expressions in the model group and vancomycin group were not significantly changed at each time-point, those in the HBD-3 group began to increase on the 1st day, and reached the peak on the 7th day and began to decline on the 14th day, and the comparative difference at each time-point was statistically significant (P<0.05); those in the HBD-3 group were significantly higher than the model group and vancomycin group at each time-point and the difference was statistically significant (P<0.05). The IL-10, TNF-α, IL-1α, and IP-10 expressions in the model group at each time were significantly higher than the other two groups and the difference was statistically significant (P<0.05); in terms of the comparison between the HBD-3 group and vancomycin group, the difference was not statistically significant (P>0.05). In conclusion, β-defensin 3 can inhibit the bacterial growth by regulating inflammation and immune responses in the MRSA-induced implant drug-resistant bacteria biofilm infection in the mouse tibial bone marrow.

The opioid antagonist, β-funaltrexamine, inhibits lipopolysaccharide-induced neuroinflammation and reduces sickness behavior in mice

Brain pathologies such as neurodegenerative diseases, infection, traumatic brain injury, and mood disorders produce enormous personal and economic burdens. It is well established that neuroinflammation plays an important role in the etiology and/or manifestation of such disorders. Previously, we discovered that beta-funaltrexamine (β-FNA) inhibits inflammatory signaling in human astrocytes in vitro, resulting in reduced expression of proinflammatory cytokines/chemokines. The present study examines the effects of peripherally administered β-FNA on lipopolysaccharide (LPS)-induced neuroinflammation and sickness behavior in vivo. Adult male C57BL/6J mice were administered β-FNA and were then immediately administered bacterial lipopolysaccharide (LPS). At 24h post-injections, sickness behavior was assessed in an open-field test. Following behavioral analysis plasma and brains were collected. Levels of interleukin-6 (IL-6), interferon-γ inducible protein-10 (CXCL10), and monocyte chemoattractant protein-1 (CCL2) were determined by enzyme-linked immunosorbant assay (ELISA). At 24h post-LPS injection, IL-6, CCL2 and CXCL10 were increased in the plasma, whereas, only CCL2 and CXCL10 were elevated in the brain. β-FNA significantly inhibited LPS-induced CXCL10 and CCL2 expression in brain, but minimally or not at all in the plasma. LPS-induced sickness behavior, as indicated by a reduction in distance moved, was prevented by β-FNA. Overall, CXCL10 expression in the brain was most positively and significantly correlated with sickness behavior; whereas, anxiety-like behavior was most positively and significantly correlated with IL-6 and CCL2 levels in the plasma and levels of CXCL10 and CCL2 in the brain. The reduction in sickness behavior may be in part due to decreased chemokine expression in the brain; further examination of the anti-inflammatory and neuroprotective effects of β-FNA is warranted.

IP-10/CXCR3 Axis Promotes the Proliferation of Vascular Smooth Muscle Cells through ERK1/2/CREB Signaling Pathway

Excessive proliferation of vascular smooth muscle cells is one of the main pathological processes leading to atherosclerosis and intimal hyperplasia after vascular interventional therapy. Our previous study has shown that interferon-γ inducible protein-10 contributes to the proliferation of vascular smooth muscle cell. However, the underlying mechanisms remain unclear. Extracellular signal-regulated kinase 1/2, serine/threonine kinase Akt, and cAMP response element binding protein are signaling pathways, which are considered to play important roles in the processes of vascular smooth muscle cell proliferation. Moreover, chemokine receptor 3 and Toll-like receptor 4 are potential receptors of inducible protein-10 in this process. In the present study, IP-10 was found to directly induce vascular smooth muscle cell proliferation, and exposure to inducible protein-10 activated extracellular signal-regulated kinase 1/2, serine/threonine kinase, and cAMP response element binding protein signaling. Inhibitor of extracellular signal-regulated kinase 1/2, rather than inhibitor of serine/threonine kinase, inhibited the phosphorylation of cAMP response element binding protein and reduced inducible protein-10-stimulated vascular smooth muscle cell proliferation. Knockdown of cAMP response element binding protein by siRNA inhibited inducible protein-10-induced vascular smooth muscle cell proliferation. Moreover, anti-CXCR3 IgG, instead of anti-Toll-like receptor 4 IgG, reduced inducible protein-10-induced vascular smooth muscle cell proliferation and inducible protein-10-stimulated extracellular signal-regulated kinase 1/2 and cAMP response element binding protein activation. Together, these results indicate that inducible protein-10 promotes vascular smooth muscle cell proliferation via chemokine receptor 3 and activation of extracellular signal-regulated kinase 1/2 inducible protein-10-induced vascular smooth muscle cell proliferation. These data provide important targets for future studies to modulate atherosclerosis and restenosis after vascular interventional therapy.

IFN-γ-INDUCED PROTEIN 10 (IP-10) IN RHEUMATOID ARTHRITIS: LITERATURE REVIEW AND THE AUTHORS' OWN DATA

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease characterized by chronic inflammation of joint synovial membrane and progressive destruction of bone and cartilage. Massive synovial infiltration with immune and inflammatory cells, such as macrophages, monocytes, granulocytes, plasma cells and dendritic cells, B lymphocytes, CD4+ and CD8+ T lymphocytes, presented mainly by effector T cells (T eff ), underlies chronic inflammation and joint destruction in RA. C-X-C-chemokine 10 (CXCL10) was originally identified as a chemokine secreted by several types of cells: macrophages, endothelial cells, and fibroblasts in response to the production of interferon-γ (IFN-γ). It is also known as IFN-γ- induced protein 10 (IP-10). It has been recently discovered that the level of CXCL10 is elevated in the serum and joint tissues of laboratory animals with collagen-induced arthritis. Patients with RA demonstrated higher serum, synovial fluid, and synovial tissue levels of IP-10 than those with osteoarthritis or healthy donors at both early and late stages of the disease. Peripheral blood IP-10, unlike acute-phase measures or indices of activity, may more accurately reflect remission status, which should be kept in mind while deciding for therapy optimization. IP-10 may be a marker for more severe disease and can be used to assess the risk of psoriatic arthritis in patients with psoriasis; its prognostic value in patients with probable RA requires further clarification. Elevated IP-10 levels may be associated with the development of interstitial lung disease in patients with RA and identified in asymptomatic early-stage patients. Thus, IP-10 may be a useful and promising prognostic marker in RA, the significance of which requires further investigation.

Inducible protein-10 as a predictive marker of antiviral hepatitis C treatment: A systematic review.

AIMTo investigate interferon-γ-inducible protein-10’s (IP-10) potential to anticipate rapid (RVR)- and sustained virological responses (SVR) to chronic hepatitis C (CHC) treatment.METHODSWe included case series examining RVR or SVR in relation to 24 or 48 wk treatment for CHC, in patients treatment free for at least six months, with genotype 1 or 4, and in relation to 24 wk treatment for genotype 2 and 3, with pegylated interferon in combination with ribavirin. Patients had to have both a baseline IP-10 level as well as a hepatitis C virus (HCV)-RNA determination 4 wk after treatment initiation or 24 wk after end of treatment. Studies including patients with liver diseases other than CHC, human immunodeficiency virus-infection, treatment with immunosuppresents or cytostatica, alcohol dependency or active intravenous drug-use were excluded. We found 81 articles by searching the MEDLINE and EMBASE databases. Eight studies were eligible for inclusion. Their quality were assesed using an 18 point checklist for case series, developed using a modified Delphi technique. Information was extracted from the articles, and no raw data was requisitioned. The review protocol was registered at the International Prospective Register of Systematic Reviews (reg. number: CRD42014008736).RESULTSThree studies reported on baseline IP-10 level in association with RVR. A signigficant association was found for HCV genotype 1 infection by two studies. Only two studies reported on HCV genotype 4 infected and genotype 2 and 3 infected patients, respectively. A trend was seen for an association between RVR and baseline IP-10 for genotype 4, while no association was found for genotype 2 and 3. Seven studies provided information regarding baseline IP-10 and SVR. Following the pattern regarding rapid virological response all five studies examining SVR in relation to baseline IP-10 levels for HCV, genotype 1 infected patients showed a significant association. Likewise a significant association was seen for HCV, genotype 4 infected, while no association was found for HCV, genotype 2 and 3 infected. Though only two studies examined the assosiation for HCV genotype 4 infected and HCV genotype 2 and 3 infected respectively.CONCLUSIONWe found indications of a possible association between baseline IP-10 level and virological responses in patients with CHC genotype 1 and 4.

A host-protein based assay to differentiate between bacterial and viral infections in preschool children (OPPORTUNITY): a double-blind, multicentre, validation study

A physician is frequently unable to distinguish bacterial from viral infections. ImmunoXpert is a novel assay combining three proteins: tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma induced protein-10 (IP-10), and C-reactive protein (CRP). We aimed to externally validate the diagnostic accuracy of this assay in differentiating between bacterial and viral infections and to compare this test with commonly used biomarkers. In this prospective, double-blind, international, multicentre study, we recruited children aged 2-60 months with lower respiratory tract infection or clinical presentation of fever without source at four hospitals in the Netherlands and two hospitals in Israel. A panel of three experienced paediatricians adjudicated a reference standard diagnosis for all patients (ie, bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. The panel was masked to the assay results. We identified majority diagnosis when two of three panel members agreed on a diagnosis and unanimous diagnosis when all three panel members agreed on the diagnosis. We calculated the diagnostic performance (ie, sensitivity, specificity, positive predictive value, and negative predictive value) of the index test in differentiating between bacterial (index test positive) and viral (index test negative) infection by comparing the test classification with the reference standard outcome. Between Oct 16, 2013 and March 1, 2015, we recruited 777 children, of whom 577 (mean age 21 months, 56% male) were assessed. The majority of the panel diagnosed 71 cases as bacterial infections and 435 as viral infections. In another 71 patients there was an inconclusive panel diagnosis. The assay distinguished bacterial from viral infections with a sensitivity of 86·7% (95% CI 75·8-93·1), a specificity of 91·1% (87·9-93·6), a positive predictive value of 60·5% (49·9-70·1), and a negative predictive value of 97·8% (95·6-98·9). In the more clear cases with unanimous panel diagnosis (n=354), sensitivity was 87·8% (74·5-94·7), specificity 93·0% (89·6-95·3), positive predictive value 62·1% (49·2-73·4), and negative predictive value 98·3% (96·1-99·3). This external validation study shows the diagnostic value of a three-host protein-based assay to differentiate between bacterial and viral infections in children with lower respiratory tract infection or fever without source. This diagnostic based on CRP, TRAIL, and IP-10 has the potential to reduce antibiotic misuse in young children. MeMed Diagnostics.

Highly Multiplexed Proteomic Analysis of Quantiferon Supernatants To Identify Biomarkers of Latent Tuberculosis Infection.

ABSTRACTThe tests for diagnosing latent tuberculosis infection (LTBI) are limited by a poor predictive value for identifying people at the highest risk for progressing to active tuberculosis (TB) and have various sensitivities and specificities in different populations. Identifying a more robust signature for LTBI is important for TB prevention and elimination. A pilot study was conducted with samples from immigrants to the United States that were screened for LTBI by the three commercially approved tests, namely, the tuberculin skin test (TST), the Quantiferon-TB Gold in-tube (QFT-GIT), and the T-SPOT.TB (T-SPOT). QFT-GIT supernatants from 13 people with concordant positive results and 26 people with concordant negative results were analyzed via the highly multiplexed SOMAscan proteomic assay. The proteins in the stimulated supernatants that distinguished LTBI from controls included interleukin-2 (IL-2), monocyte chemotactic protein 2 (MCP-2), interferon gamma inducible protein-10 (IP-10), interferon gamma (IFN-γ), tumor necrosis factor superfamily member 14 (TNFSF14, also known as LIGHT), monokine induced by gamma interferon (MIG), and granzyme B (P <0.00001). In addition, antigen stimulation increased the expression of heparin-binding EGF-like growth factor (HB-EGF) and activin AB in LTBI samples. In nil tubes, LIGHT was the most significant marker (P <0.0001) and was elevated in LTBI subjects. Other prominent markers in nonstimulated QFT-GIT supernatants were the complement-3 components C3b, iC3b, and C3d, which were upregulated in LTBI and markedly decreased upon stimulation. We found known and novel proteins that warrant further studies for developing improved tests for LTBI, for predicting progression to active disease, and for discriminating LTBI from active TB.

Uptake of parasite-derived vesicles by astrocytes and microglial phagocytosis of infected erythrocytes may drive neuroinflammation in cerebral malaria.

Astrocytes and microglia are activated during cerebral malaria (CM) and contribute to the production and release of several mediators during neuroinflammatory processes. Whether these changes are the consequence of a direct crosstalk between glial cells and the malarial parasite and how these cells participate in the pathogenesis of CM is not yet clear. We therefore examined the interaction of astrocytes and microglia with Plasmodium berghei ANKA-infected red blood cells using primary cell cultures derived from newborn C57BL/6 mice. We observed a dynamic transfer of vesicles from the parasite to astrocytes within minutes of contact, and the phagocytosis of infected red blood cells by microglia. Differential gene expression studies using the Affymetrix GeneChip® microarray, and quantitative PCR analyses showed the increase in expression of the set of genes belonging to the immune response network in parasite activated astrocytes and microglia. Interestingly, expression of these genes was also significantly upregulated in brains of mice dying from CM compared with uninfected mice or infected mice that did not develop the neuropathology. Accumulation of parasite-derived vesicles within astrocytes, and the phagocytosis of infected red blood cells by microglia induced a subsequent increase in interferon gamma inducible protein 10 (IP10) in both the brain and plasma of infected mice at the onset of CM, confirming a role for this molecule in CM pathogenesis. Altogether, these observations point to a possible role for glial cells in the neuropathological processes leading to CM. GLIA 2016 GLIA 2017;65:75-92.

Interferon-Gamma Inducible Protein-10(IP10) as a Predictor of Early Virologic Response in Chronic Hepatitis C Infected Egyptian Patients Stratified for the Interleukin-28B rs12979860 Genotyp

Background and study aim: Single nucleotide polymorphisms near Interleukin 28B are strongly associated with favourable treatment response of chronic hepatitis C such as, the homozygous CC at markers129798Session [CurrentTestPartID]. Interferon-Gamma Inducible Protein-10 (IP-10) can be produced by a variety of cells, including hepatocytes. Pre-treatment plasma levels of IP10 are elevated in patients chronically infected with hepatitis C virus of genotypes 1 or 4 who do not achieve early virological response(EVR)to treatment. The aim of this study was to evaluate the rule of adding IP-10 to IL28B rs129798Session [CurrentTestPartID] Genotype in predicting EVR . Patients and methods: The study enrolled 78 naive chronic HCV patients who have criteria that met the pegylated interferon plus ribavirin (pegIFN-RBV) treatment for chronic hepatitis C virus (HCV) .IP-10 assay and single nucleotide polymorphisms of the IL28B genotype were performed. Results: Patients with EVR was younger than those without EVR with statistically significant different. Patients with EVR had less elevated liver enzyme ,low viral load and fasting blood sugar than those without EVR with statistically significant difference. 100% patients with out early virological response had A2 activity while 31.7% only of patients with EVR had A2 activity with statistically significant difference .Patients with EVR showed lower level of IP10 and 81.7% of them had CC allele genotype with statistically significant difference when compared to patients without EVR. Patients with CC genotype were associated with lower level of IP10, ALT, AST and also low viral load. Patients with low level of IP10 had lower levels of liver enzyme. Cut off level of IP 10 was<Session [CurrentTestPartID]5 pico gram/ml; at this cut off value sensitivity was=100%, specificity was= 96.7% and area under the curve (AUC)= 0.99. Conclusion: IP10 level was lower among responder group. IL28 genotype CC was significantly higher in responders when compared with non responders. .Patients with CC genotype were associated with lower level of IP10 and liver enzymes. Patients with CC genotype were associated also with low viral load.

Intrahepatic IP-10 mRNA and plasma IP-10 levels as response marker for HBeAg-positive chronic hepatitis B patients treated with peginterferon and adefovir

IntroductionInterferon-y–inducible protein-10 (IP-10), also called CXCL10, is produced by different types of cells such as monocytes, neutrophils and hepatocytes. IP-10 functions as an inflammatory cytokine, which after binding to its receptor CXCR3, expressed on T-lymphocytes, leads to immune activation. We aimed to establish if IP-10 expression in liver tissue and in plasma of chronic hepatitis B (CHB) patients correlated with each other and further to investigate if IP-10 levels before and during therapy with peginterferon and adefovir could predict treatment outcome in CHB patients. Patients and methodsA total of 86 CHB patients (41 HBeAg-positive and 45 HBeAg-negative) received combination therapy of peginterferon and adefovir for 48 weeks. Combined Response (CR) (HBeAg-negativity, HBV-DNA ≤ 2000 IU/mL, ALT normalization) and non-response (NR) were assessed at Week 72. Plasma IP-10 levels were measured at baseline and during treatment at Day 3 (D3) and Week 1 (W1). Pre-treatment liver biopsies from 40 of 86 patients were obtained and stored in liquid nitrogen for the analysis of intrahepatic IP-10 mRNA expression. ResultsCR was achieved in 14/41 HBeAg-positive and 17/45 HBeAg-negative patients. Mean baseline plasma IP-10 levels were significantly higher in HBeAg-positive patients with CR than NR (3.20 vs 3.00 log pg/mL p = 0.03); but not in HBeAg-negative patients. Baseline IP-10 levels correlated with ALT-levels in HBeAg-positive and -negative patients (both p < 0.001), and with a decline of HBsAg-levels of ≥0.5 log IU/mL at Week 12 in HBeAg-positive patients (p = 0.001). Plasma IP-10 levels were associated with intrahepatic IP-10 mRNA expression, however, more strongly in HBeAg-positive (R = 0.79, p < 0.001) than in HBeAg-negative patients (R = 0.53, p = 0.011). IP-10 levels only correlated with HAI-scores in HBeAg-positive patients (R = 0.40 p = 0.025). Mean plasma IP-10 levels of both HBeAg-positive and -negative patients increased significantly at D3 compared to baseline (+0.30 log pg/mL p = 0.003), to then decline subsequently at W1 to a level still significantly higher than baseline (+0.14 log pg/mL p < 0.001). The increase of IP-10 was significantly higher in HBeAg-positive patients with NR than in those with CR (+0.35 versus +0.11 log pg/mL p = 0.003). ConclusionsBaseline plasma IP-10 levels and IP-10 mRNA expression in the liver are correlated with each other, suggesting that plasma IP-10 reflects intrahepatic immune activation. Higher IP-10 levels at baseline seem to be associated with CR in HBeAg-positive patients treated with peginterferon and adefovir, but not in HBeAg-negative patients.

TLR3 signaling is impaired in small airway epithelial cells following cigarette smoke exposure.

Abstract Mainstream and second hand cigarette smoke exposures increase the risk of respiratory viral infections, especially in children and those with underlying lung disease. Epithelial cells are the primary targets for viral infection and recognize foreign pathogens through multiple Toll-like receptors (TLR). TLR3 recognizes double stranded RNA, a common intermediate in virus replication, and activates antiviral signaling pathways. We hypothesized that cigarette smoke exposure impairs TLR3 signaling in airway epithelial cells leading to an increase in susceptibility to viral infection. Primary human small airway epithelial cells were cultured at the air-liquid interface and exposed to whole cigarette smoke. Following cigarette smoke exposure, cells were treated with the TLR3 ligand polyinosinic-polycytidylic acid (poly I:C), a mimic of RNA viral infection. Levels of interferon gamma induced protein 10 (IP-10) and antiviral interferon bioactivity were measured in culture supernatants. TLR3 cleavage was investigated using the cathepsin inhibitor z-FA-FMK and protein lysates were analyzed by western blot. Our data shows that cigarette smoke exposure causes a decrease in the production of IP-10, as well as a decrease in the interferon bioactivity of culture supernatants. Western blot data indicates that cigarette smoke inhibits cleavage of TLR3. Inhibitor studies confirmed that cleavage of TLR3 was important for the production of IP-10 and interferons. These data show that cigarette smoke disrupts the production of anti-viral signaling molecules by disrupting cleavage and activation of TLR3, as well as provides a mechanistic explanation for increased susceptibility to viral infections in smokers.

Suppression of TLRs signaling pathways by 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine

Toll-like receptors (TLRs) play significant roles in recognizing the pathogen-associated molecular patterns that induce innate immunity, and subsequently, acquired immunity. In general, TLRs have two downstream signaling pathways, the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF)-dependent pathways, which lead to the activation of nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine (MNP) has been previously synthesized in our laboratory. To evaluate the therapeutic potential of MNP, its effect on signal transduction via the TLR signaling pathways was examined. MNP was shown to inhibit the activation of NF-κB and IRF3 induced by TLR agonists, as well as to inhibit the expression of cyclooxygenase-2, inducible nitric oxide synthase, and interferon inducible protein-10. MNP also inhibited the activation of NF-κB and IRF3 induced by the overexpression of downstream signaling components of the MyD88- or TRIF-dependent signaling pathways. These results suggest that MNP can modulate MyD88- and TRIF-dependent signaling pathways of TLRs, leading to decreased inflammatory gene expression.

Urinary cytokines/chemokines pattern in patients with painful bone metastases undergoing external beam radiotherapy experiencing pain flare.

External beam radiotherapy (EBRT) is a mainstay for treatment of painful bone metastases. Transient worsening of pain ("pain flare") occurs in 40% of patients. We investigated the pathophysiology of pain flare through assessment of changes in urinary cytokines/chemokines in patients receiving EBRT for painful bone metastases. Urine samples were collected from patients receiving a single 8 Gy fraction for painful bone metastases preparation, day 1 or 2 and on an additional day between days 3 to 5 post radiation. Patients completed a standardized pain and analgesic use diary daily for 10 days following radiation. Patients were deemed to have pain flare if they had a two-point increase from baseline worst pain on 0-10 scale and no decrease in analgesic intake or a 25% increase in analgesic intake with no decrease in worst pain. The Millipore Milliplex 42-Plex Cyto-kine/Chemokine Kit™ was used to measure urinary levels of a panel of cytokines/chemokines. Forty-six patients consented to the study of which 28 were evaluable (complete urine and diary data), and 83/84 urine samples were available for analysis. Pain flare was experienced by 11 patients (39%). The following cytokines/chemokines were detectable in at least 50% of the patients: EGF, fractalkine, GRO, IL-4, IL-8, interferon gamma induced protein 10 (IP-10), MCP-1, macrophage derived chemokine (MDC), PDGF-AA, sIL-2Ra, TGF-Alpha, VEGF. Comparing patients with or without pain flare EGF, fractalkine, GRO, IL-8, IP-10, MCP-1, MDC, sIL-2Ra, and TGF-alpha increased following radiation in both groups. Patients with pain flare have significant lower levels on IL-8, IP-10, and MDC over time. No specific time trend was noticed. Patients who experience pain flare appear to have a different pattern in urinary cytokine/chemokine levels than patients without pain flare. A larger study is required to confirm the possible role of cytokines/chemokines in predisposition to and/or the cause of pain flare following radiation to painful bone metastases.

Alanine aminotransferase, HCV RNA levels and pro-inflammatory and pro-fibrogenic cytokines/chemokines during acute hepatitis C virus infection.

BackgroundThis study assessed the association of alanine-aminotransferase (ALT) and hepatitis C virus (HCV) RNA levels with pro-inflammatory and pro-fibrogenic cytokines and chemokines during acute HCV infection to provide further insight into the potential HCV immunopathogenesis.MethodsParticipants in the ATAHC study, a prospective study of recent HCV infection, with detectable HCV RNA at the time of HCV detection were included. Plasma levels of 27 cytokines and chemokines were measured and their correlation with ALT and HCV RNA levels were assessed. Log10 transformed cytokines and ALT values were used in the analysis.ResultsAmong 117 individuals, the plasma levels of interferon-gamma inducible protein-10 (IP-10) and macrophage inflammatory protein-1beta (MIP-1β) were positively correlated with ALT levels (IP-10: r = 0.42, P < 0.001; MIP-1β: r = 0.29, P = 0.001) and HCV RNA levels (IP-10: rs = 0.44, P < 0.001; MIP-1β: rs = 0.43, P < 0.001). Using linear regression, after adjusting for sex, age, infection duration, symptomatic infection, HIV co-infection, interferon-lambda rs12979860 genotype, HCV genotype, and assay run, higher ALT levels (β = 0.20; 95 % CI: 0.07, 0.32; P = 0.002) and HCV RNA levels >400,000 IU/mL (vs. <8,500 IU/mL; β = 0.16; 95 % CI: 0.03, 0.28; P = 0.014) were independently associated with higher IP-10 levels. HCV RNA levels >400,000 IU/mL (vs. <8,500 IU/mL; β = 0.16; 95 % CI: 0.01, 0.31; P = 0.036) were associated with higher MIP-1β levels.ConclusionsDuring acute HCV infection, high ALT and HCV RNA levels were associated with increased IP-10 levels, while high HCV RNA levels were also associated with increased MIP-1β levels. These data suggest that IP-10 and MIP-1β may have a role in HCV immuno-pathogenesis starting early in acute HCV infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-016-0482-x) contains supplementary material, which is available to authorized users.