Macrophage Inflammatory Protein-1β Research Articles

Regulatory effects of dietary L-Arg supplementation on the innate immunity and antioxidant ability in broiler chickens

Here, we investigated the effect of dietary arginine (Arg) supplementation on innate immunity and the antioxidant ability of broiler chickens. The experiment was designed as a single-factorial arrangement (n=8 cages/treatment, six birds/cage), and we used four dietary Arg concentrations (10.0, 15.0, 20.0 or 25.0 g kg−1). On day 21, the birds were killed to obtain spleen, cecal tonsil and liver samples to determine the gene expression and antioxidant characteristics. Increasing the Arg concentration linearly decreased (P<0.05) the mRNA expression of splenic interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α). Dietary Arg supplementation quadratically decreased (P<0.05) the expression of interleukin-1b (IL-1b) and interferon-γ (IFN-γ) mRNA in the spleen. Increasing Arg concentrations linearly and quadratically reduced the expression of IL-18 mRNA in the spleen. Meanwhile, increasing dietary Arg supplementation linearly and quadratically increased the lymphotactin mRNA (P<0.05) expression, and linearly increased the macrophage inflammatory protein-1β (MIP-1β) and toll-like receptor 15 (TLR15) mRNA expression in the cecal tonsils. Dietary Arg supplementation linearly (P<0.05) increased the glutathione peroxidase (GSH-Px), catalase (CAT), and lysozyme (LZM) activities in the liver. However, the malondialdehyde (MDA) activity in the liver was not influenced by the dietary Arg concentration (P>0.05). No significant (P>0.05) effect was found on the activity of superoxide dismutase (SOD) in the liver. Thus high levels of Arg supplementation (>20.0 g kg−1) may potentially suppress the innate immunity of broiler chickens, and dietary Arg supplementation enhances the antioxidant activity in broiler chickens.

Protective effect of cinnamicaldehyde in endotoxin poisoning mice

Context: Several pharmacological studies have shown that cinnamicaldehyde (CA) has anti-inflammatory and anti-tumor effects, but no data show the effects of CA on the endotoxin poisoning.Objective: In this work, the protective effect of CA in LPS-induced endotoxin poisoning mice was investigated.Materials and methods: Mice were randomly divided into normal, LPS, LPS +5 mg/kg dexamethasone (DEX), LPS +0.132 g/kg CA, and LPS +0.264 g/kg CA group. Pretreated with CA (0.132 and 0.264 g/kg/day, respectively) for 5 consecutive days before LPS injection. Except the normal group, the other animals were intraperitoneally injected with LPS (15 mg/kg).Results: Twelve hours after LPS injection, CA significantly reduced the production of pro-inflammatory cytokines (interleukin-18, interleukin-1β, and interleukin-5) and chemokines (macrophage colony stimulating factor, macrophage inflammatory protein-1β) in serum. In addition, the histopathological study indicated that CA attenuates lung injury induced by LPS. Moreover, the numbers of neutrophils were significant decreased and the NF-κB (p65) mRNA level was reduced in lung after treated with CA.Conclusion: The present data suggest that cinnamicaldehyde can be considered as potential therapeutic candidates for the endotoxin-poisoning-related diseases such as sepsis via its anti-inflammation effects.

Transcriptome analysis reveals that insulin is an immunomodulatory hormone in common carp

Common carp (Cyprinus carpio) is a widespread freshwater fish and economically important species in China and other East Asian countries. Recent studies suggest that insulin can alter the expression of immune genes and, thus, can be regarded as an immunomodulatory hormone. To understand the mechanism of the immune response to insulin, we performed a comparative RNA-seq transcriptome analysis using livers from common carp injected with insulin (5 μg/g bodyweight) or saline as a control. After filtering the low-quality reads and removing the adaptors, the clean raw reads were assembled into 60,421 unigenes with mean length of 746.81 bp. Furthermore, 37,107 unigenes were annotated based on homology after blast search in public databases. Differentially expressed genes were identified using the fragments per kb per million fragments method and EdgeR software. In total, 782 differentially expressed genes were found. Thereinto, 444 and 338 genes were upregulated and downregulated, respectively, in the insulin-injected group. A Gene Ontology analysis indicated that these genes were concentrated in glucose metabolism, hormone secretion, andimmune system processes. Moreover, 153 enriched KEGG pathways were associated with the differentially expressed genes, including the Toll-like receptor (TLR) and nuclear factor kappa beta (NF-κB) signaling pathways. Signal transducer and activator of transcription 1 (10.56-fold), TLR3 (0.089-fold), activator protein-1 (0.007-fold), tumor necrosis factor-α (0.139-fold), and macrophage inflammatory protein-1β (0.038-fold) expression were significantly changed after the insulin injection. This study characterized the profile of genes expression response to insulin in common carp liver for the first time and provided new insight into understanding the molecular mechanism of insulin as an immunomodulatory hormone.

Increased Proinflammatory Responses of Monocytes and Plasmacytoid Dendritic Cells to Influenza A Virus Infection During Pregnancy.

Pregnancy-induced alterations in immunity may contribute to the increased morbidity associated with influenza A virus infection during pregnancy. We characterized the immune response of monocytes and plasmacytoid dendritic cells (pDCs) to influenza A virus infection in 21 pregnant and 21 nonpregnant women. In pregnant women, monocytes and pDCs exhibit an exaggerated proinflammatory immune response to 2 strains of influenza A virus, compared with nonpregnant women, characterized by increased expression of major histocompatibility complex class II (approximately 2.0-fold), CD69 (approximately 2.2-fold), interferon γ-induced protein 10 (approximately 2.0-fold), and macrophage inflammatory protein 1β (approximately 1.5-fold). This enhanced innate inflammatory response during pregnancy could contribute to pulmonary inflammation following influenza A virus infection.

Abnormalities in chemokine levels in schizophrenia and their clinical correlates

Chemokines are promising biomarkers of immune activation and inflammation, but evidence for chemokine abnormalities in schizophrenia and their relationship to clinical factors remains inconclusive. We aimed to understand chemokine-related diagnostic differences and clinical correlates using a comprehensive panel and studying a large, well-characterized sample of adults with and without schizophrenia. We studied 134 outpatients with schizophrenia or schizoaffective disorder and 112 healthy comparison (HC) individuals, 26 to 65years of age. Clinical measures were obtained, and plasma levels of 11 chemokines were assessed using multiplex immunoassay. Schizophrenia vs. HC differences were tested for each chemokine, adjusting for age, gender, body mass index, and current smoking status. We also examined whether age and gender relationships differed between diagnostic groups. Using logistic regression, we created a Chemokine Index (CI) and explored its clinical correlates. Levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1β (MIP-1β/CCL4), Eotaxin-1 (CCL11), thymus and activation-regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22) were significantly higher in persons with schizophrenia than HCs. Group differences in TARC were reduced after adjusting for covariates. The CI, a linear combination of Eotaxin-1 and MDC levels, was positively associated with age, duration of schizophrenia, and severity of negative symptoms. Levels of chemokines with neuroimmune regulatory effects were higher in individuals with schizophrenia, particularly in older and chronic patients. Treatments aimed at normalizing chemokine levels might improve mental and physical health among schizophrenia patients as they age.

New Insights into the Pro-Inflammatory Activities of Ang1 on Neutrophils: Induction of MIP-1β Synthesis and Release.

We reported the expression of angiopoietin Tie2 receptor on human neutrophils and the capacity of angiopoietins (Ang1 and Ang2) to induce pro-inflammatory activities, such as platelet-activating factor synthesis, β2-integrin activation and neutrophil migration. Recently, we observed differential effects between both angiopoietins, namely, the capacity of Ang1, but not Ang2, to promote rapid interleukin-8 synthesis and release, as well as neutrophil viability. Herein, we addressed whether Ang1 and/or Ang2 could modulate the synthesis and release of macrophage inflammatory protein-1β (MIP-1β) by neutrophils. Neutrophils were isolated from blood of healthy volunteers; intracellular and extracellular MIP-1β protein concentrations were assessed by ELISA. After 24 hours, the basal intracellular and extracellular MIP-1β protein concentrations were ≈500 and 100 pg/106 neutrophils, respectively. Treatment with Ang1 (10 nM) increased neutrophil intracellular and extracellular MIP-1β concentrations by 310 and 388% respectively. Pretreatment with PI3K (LY294002), p38 MAPK (SB203580) and MEK (U0126) inhibitors completely inhibited Ang1-mediated increase of MIP-1β intracellular and extracellular protein levels. Pretreatment with NF-κB complex inhibitors, namely Bay11-7085 and IKK inhibitor VII or with a transcription inhibitor (actinomycin D) and protein synthesis inhibitor (cycloheximide), did also abrogate Ang1-mediated increase of MIP-1β intracellular and extracellular protein levels. We validated by RT-qPCR analyses the effect of Ang1 on the induction of MIP-1β mRNA levels. Our study is the first one to report Ang1 capacity to induce MIP-1β gene expression, protein synthesis and release from neutrophils, and that these effects are mediated by PI3K, p38 MAPK and MEK activation and downstream NF-κB activation.

Magnitude and Quality of Cytokine and Chemokine Storm during Acute Infection Distinguish Nonprogressive and Progressive Simian Immunodeficiency Virus Infections of Nonhuman Primates.

NHP models of HIV infection constitute a powerful tool with which to study viral pathogenesis in order to gain critical information for a better understanding of HIV infection in humans. Here we studied progressive and nonprogressive simian immunodeficiency virus (SIV) infection models in both natural and nonnatural host NHP species. Regardless of the pathogenicity of the virus infection and regardless of the NHP species studied, the magnitude of viremia, as measured by area under the curve, during the first 4 weeks of infection correlated positively with viremia in chronic infection. The magnitude of cytokine and chemokine responses during primary infection also correlated positively with both acute-phase and chronic viremia. However, the pattern and levels of specific cytokines and chemokines produced differed between nonprogressive and progressive SIV infection models. The qualitative differences in the early immune response in pathogenic and nonpathogenic infections identified here may be important determinants of the subsequent disease course.

Tributyltin exposure alters cytokine levels in mouse serum

Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL2, IL5, IL7, IL12βp40, IL13, IL15, keratinocyte chemoattractant (KC), macrophage inflammatory protein 1β (MIP), MIP2 and regulated on activation normal T-cell-expressed and secreted (RANTES) was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1β, IL-2, IL5, IL12βp40 and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in the serum of mice exposed to TBT for less than 24 h. Levels of IL1β, IL-12 βp40, IL-5 and IL-15 were also modulated in mouse serum, depending on the specific experiment and exposure level. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1β, RANTES and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines.

Essential roles for platelets during neutrophil-dependent or lymphocyte-mediated defense against bacterial pathogens

Emerging evidence from animal models suggests that platelets may participate in a wide variety of processes including the immune response against infection. More than 200 whole blood samples from patients and healthy controls were run in the System XE-5000 analyzer, and plasma fractions were separated for the following tests by ELISA, Luminex and light scattering. We describe two mechanisms by which platelets may contribute to immune function against various bacterial pathogens based on increased mean platelet volume in gram-positive bacterial infections and increased platelet counts in gram-negative bacterial infections. Gram-negative bacteria activate platelets to recruit neutrophils, which participate in the immune response against infection. During this process, fractalkine, macrophage inflammatory protein-1β, interleukin-17A, tumor necrosis factor-α and platelet-activating factor were higher in patients infected with Escherichia coli; additionally, giant platelets were observed under the microscope. Meanwhile, we found that platelets played a different role in gram-positive bacterial infections. Specifically, they could actively adhere to gram-positive bacteria in circulation and transfer them to immune sites to promote antibacterial lymphocyte expansion. During this process, complement C3 and factor XI were more highly expressed in patients infected with Staphylococcus aureus; additionally, we detected more small platelets under the microscope. Platelets participate in the immune response against both gram-negative and gram-positive bacteria, although the mechanisms differ. These results will help us understand the complex roles of platelets during infections, and direct our use of antibiotics based on clinical platelet data.

Systemic inflammatory responses in patients with type 2 diabetes with chronic periodontitis

ObjectiveThe objective of this case–control study was to quantify the immune responsiveness in individuals with type 2 diabetes (T2D) as compared with patients without diabetes (NT2D) diagnosed with periodontitis.Research Design...

Abstract 85: Macrophage inflammatory protein-1β and interleukin 15 modulate gene expression patterns associated with prostate cancer progression

Abstract Prostate Cancer (PCa) is the second-leading cause of cancer-related deaths in the United States. Inflammation is associated with PCa development and progression. Cytokines such as macrophage inflammatory protein-1β (MIP1β or CCL4) and Interleukin 15 (IL-15) are differentially expressed in prostate cancer patients with recurrent disease (MIP1β) or recurrence-free survival (IL-15). However, the specific pathway by which these cytokines affect PCa progression is unknown. We evaluated the changes in gene expression patterns using in vivo models of prostate cancer and microarray analysis. To generate prostate tumors in vivo we used a mouse orthotopic xenograft model. Androgen-receptor-positive (AR+) cells, 22RV1, were orthotopically injected in the anterior prostate lobes. MIP1β and IL-15 were administered bi-weekly with intraperitoneal injections during 4 weeks. Tumor tissue was collected and snap frozen for RNA extraction, and microarray analysis with the Affymetrix Human Gene 2.0 Gene Array. Differences in gene expression were analyzed with Ingenuity Pathway Analysis (IPA) software and confirmation was done via real-time PCR. Microarray analysis showed 179 genes differentially expressed between MIP1β and control. In addition, 952 genes were differentially expressed between IL-15 and control. Ingenuity Pathway Analysis revealed that MIP1β affected networks associated with cell development, proliferation and movement while IL-15 affected networks involved in lymphocyte development and movement, cell death, and the inhibition of cancer cell invasion. Knowledge of the role of MIP1β and IL-15 in the alteration of gene expression patterns is pertinent to elucidate the significance of these cytokines in prostate cancer progression. Citation Format: Krizia Rohena-Rivera, Diana A. Aponte-Colón, María M. Sánchez-Vázquez, Carmen L. Cadilla, Magaly Martínez-Ferrer. Macrophage inflammatory protein-1β and interleukin 15 modulate gene expression patterns associated with prostate cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 85.

Circulating Levels of the Adipokines Monocyte Chemotactic Protein-4 (MCP-4), Macrophage Inflammatory Protein-1β (MIP-1β), and Eotaxin-3 in Severe Obesity and Following Bariatric Surgery

The aim of the study was to investigate the involvement of the adipokines eotaxin-3, MIP-1β, and MCP-4 in obesity and related comorbidities and the modification of their circulating levels after bariatric surgery. Eighty severely obese subjects and 20 normal-weight controls were included in the study. Circulating levels of MCP-4, MIP-1β, and eotaxin-3, and the main clinical, biochemical, and instrumental parameters for the evaluation of cardiovascular and metabolic profile were determined in controls and in obese subjects at baseline and 10 months after surgery. Within the obese group at baseline, eotaxin-3 levels were higher in males than females and in smokers than non-smokers and showed a positive correlation with LDL-cholesterol, apolipoprotein B, and leptin. MIP-1β showed a positive correlation with age and leptin and a negative correlation with adiponectin and was an independent predictor of increased carotid artery intima-media thickness. MCP-4 levels were higher in obese subjects than controls and showed a positive correlation with body mass index, eotaxin-3, and MIP-1β. Bariatric surgery induced a marked decrease in all the 3 adipokines. MCP-4 is a novel biomarker of severe obesity and could have an indirect role in favoring sub-clinical atherosclerosis in obese patients by influencing the circulating levels of eotaxin-3 and MIP-1β, which are directly related to the main atherosclerosis markers and risk factors. The reduction of circulating levels of MCP-4, eotaxin-3, and MIP-1β could be one of the mechanisms by which bariatric surgery contributes to the reduction of cardiovascular risk in these patients.

Association between subchronic and chronic lead exposure and levels of antioxidants and chemokines.

PurposeThis study aimed to compare the influence of lead on the non-enzymatic antioxidant defenses and the levels of chemokines in workers subchronically and chronically exposed to lead.MethodsThe study population was divided into three groups. The first group consisted of male workers subchronically exposed to lead for 40 ± 3.2 days, while the second group included male workers chronically exposed to lead. The third group was a control group.ResultsThe levels of uric acid and bilirubin were significantly higher after a subchronic exposure to lead compared to the baseline by 22 and 35 %, respectively. Similarly, the values of total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) increased by 15, 50, and 33 %, respectively. At the same time, the levels of thiol groups and albumin decreased by 5 and 8 %, respectively. Additionally, the levels of interleukin-8 (IL-8) and macrophage inflammatory protein-1β (MIP-1β) were significantly higher after a subchronic exposure to lead compared to the baseline by 34 and 20 %, respectively. Moreover, IL-8 level was significantly higher by 40 % in the group of workers chronically exposed to lead than in the control group, while the level of interferon gamma-induced protein-10 (IP-10) was significantly lower by 28 %.ConclusionsSimilar to chronic lead exposure, subchronic exposure to lead is associated with elevated blood levels of uric acid and bilirubin in humans. This probably results in increased TAC value despite thiol depletion. However, the compensatory activation of non-enzymatic antioxidant defenses seems to be insufficient to protect against lead-induced oxidative stress, which may be additively enhanced by the pro-inflammatory action of chemokines, especially IL-8.

Cytokine and Chemokine Signature in Elite Versus Viremic Controllers Infected with HIV.

HIV long-term nonprogressors (LTNPs) maintaining high CD4(+) T-cell counts without antiretroviral therapy (ART) are divided into elite controllers (ECs) with undetectable and viremic controllers (VCs) with low viral loads. Little is known about the long-term changes of T-cell subsets and inflammation patterns in ECs versus VCs. The aim of the study was to explore the long-term evolution of CD4(+) T-cell levels in LTNPs and to analyze cytokine profiles in ECs versus VCs. Nineteen ECs and 15 VCs were enrolled from the natural virus controller cohort (NaViC). T-cell counts were monitored over years, the mean annual change was calculated, and plasma concentrations of 25 cytokines were evaluated using a multiplex bead array. While absolute numbers of T cells did not differ between ECs and VCs over time, we observed a significant decrease of CD4(+) T-cell percentages in VCs, but not in ECs (median [interquartile range]: ECs: 37% [28-41] vs. VCs: 29% [25-34]; p = .02). ECs had lower levels of macrophage inflammatory protein-1β (MIP-1β, p = .003), interferon γ-induced protein-10 (IP-10, p = .03), and monokine induced by interferon-γ (MIG, p = .02). CD4(+) T-cell percentages inversely correlated with MIP 1-β (r = -0.42, p = .017) and IP-10 (r = -0.77, p < .0001). A subtle decline of CD4(+) T-cell percentages could be observed in VCs, but not in ECs, which was associated with higher plasma levels of proinflammatory cytokines. Hence, even low levels of HIV replication might go along with a progressive decline in CD4(+) T-cell counts in LTNPs.

Immunostimulating and Gram-negative-specific antibacterial cyclotides from the butterfly pea (Clitoria ternatea).

Cyclotides are plant-derived, cyclic miniproteins with three interlocking disulfide bonds that have attracted great interests because of their excellent stability and potential as peptide therapeutics. In this study, we characterize the cyclotides of the medicinal plant Clitoria ternatea (butterfly pea) and investigate their biological activities. Using a combined proteomic and transcriptomic method, we identified 41 novel cyclotide sequences, which we named cliotides, making C. ternatea one of the richest cyclotide-producing plants to date. Selected members of the cationic cliotides display potent antibacterial activity specifically against Gram-negative bacteria with minimal inhibitory concentrations as low as 0.5 μm. Remarkably, they also possess prominent immunostimulating activity. At a concentration of 1 μm, cationic cliotides are capable of augmenting the secretion of various cytokines and chemokines in human monocytes at both resting and lipopolysaccharide-stimulated states. Chemokines such as macrophage inflammatory proteins 1α and 1β, interferon γ-induced protein 10, interleukin 8 and tumor necrosis factor α were among the most upregulated with up to 129-fold increase in secretion level. These findings suggest cyclotides can serve as potential candidates for novel immunomodulating therapeutics. The protein sequences reported in this paper (cT13-cT21) are available in the UniProt Knowledgebase under the accession numbers C0HJS0, C0HJS1, C0HJS2, C0HJS3, C0HJS4, C0HJS5, C0HJS6, C0HJS7 and C0HJS8, respectively. The transcriptome data in this paper are available at the Sequence Read Archive database (NCBI) under accession number SRR1613316. The protein precursors reported in this paper (ctc13, ctc15, ctc17-ctc19, ctc21-ctc53) are available at GenBank under the accession numbers KT732712, KT732713, KT732714, KT732715, KT732716, KT732717, KT732718, KT732719, KT732720, KT732721, KT732722, KT732723, KT732724, KT732725, KT732726, KT732727, KT732728, KT732729, KT732730, KT732731, KT732732, KT732733, KT732734, KT732735, KT732736, KT732737, KT732738, KT732739, KT732740, KT732741, KT732742, KT732743, KT732744, KT732745, KT732746, KT732747, KT732748 and KT732749, respectively.

CCL4 as an adjuvant for DNA vaccination in a Her2/neu mouse tumor model.

Chemokines are key regulators of both innate and adaptive immune responses. CCL4 (macrophage inflammatory protein-1β, MIP-1β) is a CC chemokine that has a broad spectrum of target cells including immature dendritic cells, which express the cognate receptor CCR5. We asked whether a plasmid encoding CCL4 is able to improve tumor protection and immune responses in a Her2/neu+ mouse tumor model. Balb/c mice were immunized twice intramuscularly with plasmid DNA on days 1 and 15. On day 25, a tumor challenge was performed with 2 × 10(5) syngeneic Her2/neu+ D2F2/E2 tumor cells. Different groups of mice were vaccinated with pDNA(Her2/neu) plus pDNA(CCL4), pDNA(Her2/neu), pDNA(CCL4) or mock vector alone. Our results show that CCL4 is able to (i) improve tumor protection and (ii) augment a TH1-polarized immune response against Her2/neu. Although Her2/neu-specific humoral and T-cell immune responses were comparable with that induced in previous studies using CCL19 or CCL21 as adjuvants, tumor protection conferred by CCL4 was inferior. Whether this is due to a different spectrum of (innate) immune cells, remains to be clarified. However, combination of CCL19/21 with CCL4 might be a reasonable approach in the future, particularly for DNA vaccination in Her2/neu+ breast cancer in the situation of minimal residual disease.

A multiplexed analysis approach identifies new association of inflammatory proteins in patients with overactive bladder

Overactive bladder (OAB) is a common debilitating bladder condition with unknown etiology and limited diagnostic modalities. Here, we explored a novel high-throughput and unbiased multiplex approach with cellular and molecular components in a well-characterized patient cohort to identify biomarkers that could be reliably used to distinguish OAB from controls or provide insights into underlying etiology. As a secondary analysis, we determined whether this method could discriminate between OAB and other chronic bladder conditions. We analyzed plasma samples from healthy volunteers (n = 19) and patients diagnosed with OAB, interstitial cystitis/bladder pain syndrome (IC/BPS), or urinary tract infections (UTI; n = 51) for proinflammatory, chemokine, cytokine, angiogenesis, and vascular injury factors using Meso Scale Discovery (MSD) analysis and urinary cytological analysis. Wilcoxon rank-sum tests were used to perform univariate and multivariate comparisons between patient groups (controls, OAB, IC/BPS, and UTI). Multivariate logistic regression models were fit for each MSD analyte on 1) OAB patients and controls, 2) OAB and IC/BPS patients, and 3) OAB and UTI patients. Age, race, and sex were included as independent variables in all multivariate analysis. Receiver operating characteristic (ROC) curves were generated to determine the diagnostic potential of a given analyte. Our findings demonstrate that five analytes, i.e., interleukin 4, TNF-α, macrophage inflammatory protein-1β, serum amyloid A, and Tie2 can reliably differentiate OAB relative to controls and can be used to distinguish OAB from the other conditions. Together, our pilot study suggests a molecular imbalance in inflammatory proteins may contribute to OAB pathogenesis.

A Nonhematopoietic Erythropoietin Analogue, ARA 290, Inhibits Macrophage Activation and Prevents Damage to Transplanted Islets.

Erythropoietin exerts anti-inflammatory, antiapoptotic, and cytoprotective effects in addition to its hematopoietic action. A nonhematopoietic erythropoietin analogue, ARA 290, has similar properties. The efficacy of pancreatic islet transplantation (PITx) is reduced due to islet damage that occurs during isolation and from the severe inflammatory reactions caused by the transplantation procedure. We investigated whether ARA 290 protects islets and ameliorates inflammatory responses following PITx thus improving engraftment. The effects of ARA 290 on pancreatic islets of C57BL/6J (H-2) mice and on murine macrophages were investigated using an in vitro culture model. As a marginal PITx, 185 islets were transplanted into the liver of streptozotocin-induced diabetic mice (H-2) via the portal vein. Recipients were given ARA 290 (120 μg/kg) intraperitoneally just before and at 0, 6, and 24 hours after PITx. Liver samples were obtained at 12 hours after PITx, and expression levels of proinflammatory cytokines were assessed. ARA 290 protected islets from cytokine-induced damage and apoptosis. Secretion of pro-inflammatory cytokines (IL-6, IL-12, and TNF-α) from macrophages was significantly inhibited by ARA 290. After the marginal PITx, ARA 290 treatment significantly improved the blood glucose levels when compared to those of control animals (P < 0.001). Upregulation of monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, IL-1β, and IL-6 messenger RNA expression within the liver was suppressed by ARA 290 treatment. ARA 290 protected pancreatic islets from cytokine-induced damage and apoptosis and ameliorated the inflammatory response after PITx. ARA 290 appears to be a promising candidate for improvement of PITx.

Host innate inflammatory factors and staphylococcal protein A influence the duration of human Staphylococcus aureus nasal carriage.

Human Staphylococcus aureus (SA) nasal carriage provides a reservoir for the dissemination of infectious strains; however, factors regulating the establishment and persistence of nasal colonization are mostly unknown. We measured carriage duration and nasal fluid inflammatory markers after nasally inoculating healthy participants with their previously isolated SA strains. Ten out of 15 studies resulted in rapid clearance (9±6 days) that corresponded with upregulated chemokines, growth factors, and predominantly Th1-type cytokines, but not IL-17. Nasal SA persistence corresponded with elevated baseline levels of MIP-1β, IL-1β, and IL-6, no induction of inflammatory factors post-inoculation, and decreased IL-1RA:IL-1β ratio. SA-expressed staphylococcal protein A (SpA) levels correlated positively with carriage duration. Competitive inoculation studies revealed that isogenic SpA knockout (ΔSpA) strains were cleared faster than wild-type only in participants with upregulated inflammatory markers post-inoculation. The remaining participants did not mount an inflammatory response and did not clear either strain. ΔSpA strains demonstrated lower growth rates in carrier nasal fluids and lower survival rates when incubated with neutrophils. Collectively, the presented studies identify innate immune effectors that cooperatively modulate nasal carriage duration, and confirm SpA as a bacterial co-determinant of SA nasal carriage.

Responses of the Toll-like receptor and melanoma differentiation-associated protein 5 signaling pathways to avian infectious bronchitis virus infection in chicks.

Avian infectious bronchitis virus (IBV) is a Gammacoronavirus in the family Coronaviridae and causes highly contagious respiratory disease in chickens. Innate immunity plays significant roles in host defense against IBV. Here, we explored the interaction between IBV and the host innate immune system. Severe histopathological lesions were observed in the tracheal mucosa at 3-5 days post inoculation (dpi) and in the kidney at 8 dpi, with heavy viral loads at 1-11 and 1-28 dpi, respectively. The expression of mRNAs encoding Toll-like receptor (TLR) 3 and TLR7 were upregulated at 3-8 dpi, and that of TIR-domain-containing adapter-inducing interferon (IFN) β (TRIF) was upregulated at 21 dpi in the trachea and kidney. Myeloid differentiation primary response protein 88 (MyD88) was upregulated in the trachea during early infection. Tumor necrosis factor receptor-associated factor (TRAF) 3 and TRAF6 were upregulated expression in both tissues. Moreover, melanoma differentiation-associated protein 5 (MDA5), laboratory of genetics and physiology 2 (LGP2), stimulator of IFN genes (STING), and mitochondrial antiviral signaling protein (MAVS), as well as TANK binding kinase 1 (TBK1), inhibitor of kappaB kinase (IKK) ε, IKKα, IKKβ, IFN regulatory factor (IRF) 7, nuclear factor of kappaB (NF-ĸB), IFN-α, IFN-β, various interleukins(ILs), and macrophage inflammatory protein-1β (MIP-1β) were significantly upregulated in the trachea and downregulated in the kidney. These results suggested that the TLR and MDA5 signaling pathways and innate immune cytokine were induced after IBV infection. Additionally, consistent responses to IBV infection were observed during early infection, with differential and complicated responses in the kidney.