High amniotic fluid fractalkine and MIP-1ß levels are associated with intrauterine growth restriction: a prospective cohort study.

Background/aim: Proinflammatory chemokines have been shown to play crucial roles in implantation, spiral artery invasion, and the fetomaternal immunological response. In this context, we investigated the levels of fractalkine (CX3CL1) and chemokine CC motif ligand 4 (CCL4 or MIP-1ß) in maternal serum and amniotic fluids in pregnant women with intrauterine growth restriction (IUGR). Materials and methods: This prospective cohort study was carried out at Firat University Obstetrics Clinic between January 1, 2022 and July 1, 2022. Group (G) 1: The control group consisted of 40 pregnant women who underwent elective cesarean section (CS) at 38-40 weeks of gestation. G2: A total of 40 pregnant women with IUGR at 28-37 weeks of gestation were included in the study group. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), interferon-gamma (IFN-γ), hypoxia-inducible factor-1 alpha (HIF-1α), macrophage inflammatory protein-1 beta (MIP-1ß), and fractalkine were measured in maternal serum and amniotic fluid samples obtained during CS. Results: When maternal age was compared, no statistically significant difference was observed between G1 and G2 (p = 0.374). The number of gravidity was found to be statistically higher in G1 compared to G2 (p = 0.003). The mean gestational week was statistically higher in G1 (p < 0.001). Maternal serum MIP-1ß (p = 0.03) and IFN-γ (p = 0.006) levels were higher in G1. The birth weight of the baby (p < 0.001) and umbilical cord blood gas pH value (p < 0.001) at birth were higher in G1. HIF-1α (p < 0.001), fractalkine (p < 0.001), MIP-1ß (p < 0.001), TNF-α (p = 0.007), IL-1ß (p < 0.001), and IFN-γ levels (p = 0.007) in amniotic fluid were higher in G2. Conclusion: Elevated levels of proinflammatory factors, including fractalkine and MIP-1ß, along with inflammatory factors such as TNF-α, IL-1ß, and IFN-γ, as well as increased HIF-1α levels in amniotic fluid, are associated with intrauterine growth restriction (IUGR) attributed to a hypoxic amniotic environment.

Changes in serum DAMPs and cytokines/chemokines during near-infrared photoimmunotherapy for patients with head and neck cancer.

BACKGROUND: Near-infrared photoimmunotherapy (NIR-PIT) for head and neck cancer is a recently developed therapy. However, there is limited data on patients receiving NIR-PIT in real clinical settings. METHODS: Seven NIR-PIT sessions were administered to five patients with head and neck squamous cell carcinoma (HNSCC). Serum damage-associated molecular patterns (DAMPs) (HMGB1 and Hsp70 levels), and cytokine and chemokine production, were compared before and after NIR-PIT. RESULTS: The serum concentration of HMGB1 increased after NIR-PIT (p = 0.031, Wilcoxon test) in all patients except one who did not achieve a clinical response. Chemokines MIP-1α (CCL3) and MIP-1ß (CCL4) increased significantly 1-3 days after treatment (CCL3, p = 0.0036; CCL4, p = 0.0016, Wilcoxon test). A low pre-treatment neutrophil-to-lymphocyte ratio (NLR) was associated with a better response to therapy and survival. CONCLUSIONS: The release of DAMPs, and cytokine/chemokine production, were detected in the patients' peripheral blood. The baseline NLR may predict patient outcomes in response to NIR-PIT.

Combined Gemcitabine and Immune-Checkpoint Inhibition Conquers Anti-PD-L1 Resistance in Low-Immunogenic Mismatch Repair-Deficient Tumors.

Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches are warranted. Herein, we applied a combined regimen with an α-PD-L1 antibody and gemcitabine in a preclinical tumor model to activate endogenous antitumor immune responses. Mlh1-/- mice with established gastrointestinal tumors received the α-PD-L1 antibody (clone 6E11; 2.5 mg/kg bw, i.v., q2wx3) and gemcitabine (100 mg/kg bw, i.p., q4wx3) in mono- or combination therapy. Survival and tumor growth were recorded. Immunological changes in the blood were routinely examined via multi-color flow cytometry and complemented by ex vivo frameshift mutation analysis to identify alterations in Mlh1-/--tumor-associated target genes. The combined therapy of α-PD-L1 and gemcitabine prolonged median overall survival of Mlh1-/- mice from four weeks in the untreated control group to 12 weeks, accompanied by therapy-induced tumor growth inhibition, as measured by [18F]-FDG PET/CT. Plasma cytokine levels of IL13, TNFα, and MIP1ß were increased and also higher than in mice receiving either monotherapy. Circulating splenic and intratumoral myeloid-derived suppressor cells (MDSCs), as well as M2 macrophages, were markedly reduced. Besides, residual tumor specimens from combi-treated mice had increased numbers of infiltrating cytotoxic T-cells. Frameshift mutations in APC, Tmem60, and Casc3 were no longer detectable upon treatment, likely because of the successful eradication of single mutated cell clones. By contrast, novel mutations appeared. Collectively, we herein confirm the safe application of combined chemo-immunotherapy by long-term tumor growth control to prevent the development of resistance mechanisms.

Cytokine and Chemokine Profile in Patients with Multiple Myeloma Treated with Bortezomib.

The aim of the study was to determine the levels of selected cytokines and chemokines in the serum of multiple myeloma (MM) patients treated with bortezomib-based regimens. A total of 71 MM patients were examined: 41 with primary refractory disease (17) or early relapse (28), and 30 who were bortezomib sensitive with no progression for at least six months. Patients who demonstrated CR or PR after bortezomib-based therapies longer than six months after treatment discontinuation were designated bortezomib sensitive. Serum cytokine levels were assayed with Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay on the MAGPIX Multiplex Reader and the Bio-Plex® 200 System (Bio-Rad). Higher levels of MIP-1α and lower levels of MIP-1ß and IL-9 were associated with better responses to bortezomib-based treatment, and higher levels of IL-1ra and IL-8 were associated with bone involvement. MCP-1 was elevated in patients with hemoglobin < 10 g/dl compared to those without anemia. The levels of IL-8, MIP-1α, and TNF-α were significantly higher in patients with renal insufficiency. Only MIP-1α was elevated in patients with hypercalcemia compared to patients with normal calcium levels. In conclusion, distinct cytokines are involved in the pathogenesis of MM and may play a prominent role in the prediction of treatment response. However, a single measurement of serum cytokines should be interpreted with caution and further studies are needed.

Bone Marrow Plasma Cytokine Signature Profiles in Severe Aplastic Anemia.

OBJECTIVE: We studied bone marrow plasma (BMP) cytokines in severe aplastic anemia (SAA) patients and healthy volunteers to investigate differences in the cytokine profiles between them and propose a cytokine signature of SAA. METHODS: A Bio-Plex suspension array system was used to measure 27 analytes in BMP samples from 47 SAA patients and 30 healthy donors. RESULTS: Compared to healthy people, SAA patients had higher levels of tumor necrosis factor α (TNF-α (TNF-γ (IFN-γ (IFN-ß (MIP-1ß (MIP-1α (TNF-α (TNF-ß (MIP-1ß (MIP-1ß (MIP-1γ (IFN-α (TNF. CONCLUSIONS: The current study demonstrated distinct cytokine profiles among untreated SAA patients, recovering SAA (RSAA) patients, and healthy people. The cytokines of RSAA patients showed similar characteristics to those of untreated SAA patients and healthy people, respectively, which may reflect that the immune status of RSAA patients is in different stages of recovery after IST; thus, it may provide an important tool in diagnosing and evaluating or predicting curative effects in clinics.

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer's disease.

BACKGROUND: Studies suggest a role of the innate immune system, including the activity of neutrophils, in neurodegeneration related to Alzheimer's disease (AD), but prospective cognitive data remain lacking in humans. We aimed to investigate the predictive relationship between neutrophil-associated inflammatory proteins in peripheral blood and changes in memory and executive function over 1 year in patients with AD. METHODS: Participants with AD were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1ß), and tumor necrosis factor (TNF) were assayed by luminex immunofluorescence multiplex assay at baseline. Confirmatory factor analysis was used to test an underlying neutrophil associated plasma inflammatory factor. Composite z-scores for memory and executive function were generated from multiple tests at baseline and at 1 year. A multiple linear regression model was used to investigate the association of the baseline inflammatory factor with changes in memory and executive function over 1 year. RESULTS: Among AD patients (n = 109, age = 74.8 ± 8.1, 42% women, Mini Mental State Examination [MMSE] = 23.6 ± 1.9), the neutrophil-related inflammatory proteins NGAL (λ = 0.595, p < .001), MPO (λ = 0.575, p < .001), IL-8 (λ = 0.525, p < .001), MIP-1ß (λ = 0.411, p = .008), and TNF (λ = 0.475, p < .001) were found to inform an underlying factor. Over 1 year, this inflammatory factor predicted a decline in executive function (ß = - 0.152, p = 0.015) but not memory (ß = 0.030, p = 0.577) in models controlling for demographics, brain atrophy, white matter hyperintensities, the ApoE ε4 allele, concomitant medications, and baseline cognitive performance. CONCLUSIONS: An inflammatory factor constructed from five neutrophil-related markers in peripheral blood predicted a decline in executive function over 1 year in people with mild AD.

IL-17A Contributes to Lung Fibrosis in a Model of Chronic Pulmonary Graft-versus-host Disease.

BACKGROUND: Chronic pulmonary graft-versus-host disease (cpGVHD) after hematopoietic cell transplant (HCT) manifests as progressive airway and parenchymal lung fibrosis. On the basis of our prior data, mice that undergo allogeneic HCT with Tbet-knockout donors (AlloTbet) have increased lung Th17 cells and IL-17A and develop fibrosis resembling human cpGVHD. The role of IL-17A in posttransplant pulmonary fibrosis remains incompletely understood. We hypothesized that IL-17A is necessary for development of murine cpGVHD in this model. METHODS: AlloTbet mice received weekly intraperitoneal anti-IL-17A or IgG (200 µg/mouse) starting 2 weeks post-HCT and were sacrificed after week 5. Histologic airway and parenchymal fibrosis were semiquantitatively graded in a blinded fashion. Lung cells and proteins were measured by flow cytometry, ELISA, and multicytokine assays. RESULTS: Anti-IL-17A modestly decreased airway and parenchymal lung fibrosis, along with a striking reduction in pulmonary neutrophilia, IL-6, MIP-1α, MIP-1ß, CXCL1, and CXCL5 in AlloTbet mice. Additionally, anti-IL-17A decreased CCL2, inflammatory monocytes and macrophages, and Th17 cells. CONCLUSIONS: In the setting of murine AlloHCT with Tbet donors, IL-17A blockade decreases fibrotic features of cpGVHD. This may be mediated by the observed reduction in neutrophils or specific lung monocyte and macrophage populations or alternatively via a direct effect on fibroblasts. Collectively, our results further suggest that anti-IL-17A strategies could prove useful in preventing alloimmune-driven fibrotic lung diseases.

The clinical value of IL-3, IL-4, IL-12p70, IL17A, IFN-γ, MIP-1ß, NLR, P-selectin, and TNF-α in differentiating bloodstream infections caused by gram-negative, gram-positive bacteria and fungi in hospitalized patients: An Observational Study.

Early differential diagnosis of bloodstream infections (BSIs) caused by different sources and species of bacteria in hospitalized patients is crucial for the timely targeted interventions including appropriate use of antibiotics. The aim of this study was to identify 9 biomarkers for the early differentiation of gram-negative-bloodstream infection (GN-BSI), gram-positive (GP)-BSI, and fungal-BSI.A prospective study was conducted for a total of 390 inpatients who underwent blood culture in the Chinese PLA General Hospital from September 2015 to March 2018. Patients with positive culture of a single pathogen were divided into GN-BSI, GP-BSI, and Fungal-BSI groups, and a culture-negative disease control group was also established. The serum levels of macrophage inflammatory protein 1ß (MIP-1ß), tumor necrosis factor α (TNF-α), interleukin (IL)-3, interferon (IFN)-γ, IL-17A, IL-4, IL-12p70, and P-selectin were detected and the NLR was calculated from routine blood test. Receiver-operating characteristic analysis was used to determine the efficacy of various indicators in the differential diagnosis of BSIs. Prediction and validation experiments on clinical patient samples (263 cases) were also performed.The level of IL-3 in the GP-BSI group was significantly higher than those in the other 3 groups. The level of IFN-γ in the fungal-BSI group was significantly higher than those in the other 3 groups. NLR, MIP-1ß, TNF-α, IL-17A, and IL3 exhibited some efficacy when distinguishing between GN-BSI and GP-BSI and NLR had the largest area under curve (AUC) (0.728), followed by MIP-1ß with an AUC of 0.679. IFN-γ and IL-3 exhibited some value in differential diagnosis between GN-BSI and Fungal-BSI. IL-3, MIP-1ß, TNF-α, IFN-γ, NLR, IL-17A, and IL-4 exhibited some value in distinguishing fungal-BSI and GP-BSI, with IL-3 had the largest AUC (0.722), followed by MIP-1ß with an AUC of 0.703.NLR and MIP-1ß may be valuable in differentiating GN-BSI from GP-BSI in hospitalized patients. IFN-γ and IL-3 may be helpful in differential diagnosis GN-BSI and fungal-BSI. IL-3 and MIP-1ß exhibited some diagnostic efficacy in distinguishing fungal-BSI and GP-BSI. Additionally, IL-3 with high serum level may be a marker for GP-BSI and IFN-γ with high serum level may be a valuable marker for the prediction of Fungal-BSI. The utility of these biomarkers to predict BSIs owing to different pathogens in hospitalized patients needs to be assessed in further studies.

Serological landscape of cytokines in cutaneous melanoma.

BACKGROUND: To date, serological markers to monitor melanoma progression and response to therapy are lacking. In this context cytokines appear to be promising biomarkers of the disease. OBJECTIVE: To compare cytokine and chemokine levels in melanoma patients and in healthy controls and to assess possible variations according to melanoma stage. METHODS: Serum chemokine and cytokine levels were determined by ELISA in 34 patients diagnosed histologically of malignant melanoma. Seven healthy volunteers were used as controls. RESULTS: We found a subset of cytokines (CCL3, CCL4, IFN-γ and IL-10) to be significantly higher in melanoma patients than in control group, thus confirming the importance of the inflammation in cancer. While CCL3 increased with tumor progression, IFN-γ and IL-10 showed higher levels in stage I patients. Moreover, we noticed a direct correlation between CCL3 level and the presence of ulceration in the primary tumor; on the contrary, CCL4, IL-10 and IFN-γ were lowered down in patients with ulcerated melanoma. CONCLUSIONS: These results expand and confirm observations made in other studies focusing on a more limited number of molecules. This extended panel of cytokines examines the potential roles of type2 cytokines (such as IL-4) and many chemokines (mainly CCL3) as biomarkers in melanoma progression.

CCR5/CCR5 ligand-induced myeloid-derived suppressor cells are related to the progression of endometriosis.

RESEARCH QUESTION: Immunological disorders have been reported to promote the progression of endometriosis. Several recent studies have shown that myeloid-derived suppressor cells (MDSC) drive the progression of endometriosis. The aim of this case-control study was to test whether CCR5 and its ligands drive MDSC accumulation and play a role in the progression of endometriosis. DESIGN: Thirty-six endometriosis patients and 20 controls were recruited. All subjects underwent laparoscopy. An ELISA kit was used to define CCR5 ligands in plasma and peritoneal fluid from endometriosis patients; flow cytometry was then used to characterize CCR5+MDSC in peripheral blood and peritoneal fluid. RESULTS: Data showed that endometriosis patients displayed a significantly higher production of plasma CCL3 (P = 0.046) and peritoneal fluid CCL3/5 (P = 0.042/0.036) compared with those from the uterine leiomyoma group. Furthermore, the concentrations of peritoneal fluid CCL5 were elevated in late stage patients compared with those from the uterine leiomyoma group. Accumulation of blood CCR5+Mo-MDSC was detected in endometriosis patients compared with those from both the ovarian dermoid cysts and uterine leiomyoma groups. Endometriosis patients also showed an elevation of CCR5+MDSC and CCR5+Mo-MDSC in peritoneal fluid samples compared with uterine leiomyoma samples. It was also found that enrichment of CCR5+MDSC (r = 0.6807; P < 0.0001) and CCR5+Mo-MDSC (r = 0.6893; P < 0.0001) were correlated with enhanced production of CCL5 in peritoneal fluid from endometriosis patients. CONCLUSIONS: This study showed that CCR5 and its ligands could drive the progression of endometriosis by enhancing the accumulation of MDSC. These findings might produce a promising treatment that targets CCR5+MDSC for endometriosis patients.

Effect of antidepressant treatment on plasma levels of neuroinflammation-associated molecules in patients with somatic symptom disorder with predominant pain around the orofacial region.

OBJECTIVE: Burning mouth syndrome (BMS) and atypical odontalgia (AO) are examples of somatic symptom disorders with predominant pain around the orofacial region. Neuroinflammation is thought to play a role in the mechanisms, but few studies have been conducted. We aimed to better understand the role of neuroinflammation in the pathophysiology and treatment of BMS/AO. METHODS: Plasma levels of 28 neuroinflammation-related molecules were determined in 44 controls and 48 BMS/AO patients both pretreatment and 12-week post-treatment with duloxetine. RESULTS: Baseline plasma levels of interleukin (IL)-1ß (p < .0001), IL-1 receptor antagonist (p < .001), IL-6 (p < .0001), macrophage inflammatory protein-1ß (p < .0001), and platelet-derived growth factor-bb (.04) were significantly higher in patients than in controls. Plasma levels of granulocyte macrophage colony stimulating factor were significantly higher in patients than in controls (p < .001) and decreased with treatment (.009). Plasma levels of eotaxin, monocyte chemoattractant protein-1, and vascular endothelial growth factor decreased significantly with treatment (p < .001, .022, and .029, respectively). CONCLUSIONS: Inflammatory mechanisms may be involved in the pathophysiology and/or treatment response of somatic symptom disorders with predominant pain around the orofacial region.

Systemic inflammatory burden and local inflammation in periodontitis: What is the link between inflammatory biomarkers in serum and gingival crevicular fluid?

In periodontitis patients, high levels of several inflammatory markers may be expressed in serum, reflecting the effect of local disease on the general health. The objective of the present analysis was to compare cytokine levels assessed in peripheral blood with those in the gingival crevicular fluid (GCF) and evaluate the impact of nonsurgical periodontal therapy on the incidence of high levels of 12 biomarkers in serum. Twenty-four patients with chronic periodontitis (Group P) contributed with serum and GCF samples at baseline (BL) and 1 and 3 months after periodontal treatment (M1 and M3). Samples were assessed for 12 cytokines using the Bio-Plex bead array multianalyte detection system. For each analyte, peak values were calculated as greater than the mean + 2SD of the one found in 60 periodontally healthy participants. Significant correlations between serum and GCF values were obtained in the periodontitis group for interleukin (IL) 1ra, IL-6, and interferon γ at BL and for macrophage inflammatory protein 1ß at M3 after treatment. Periodontitis subjects were found to exhibit high peaks for several inflammatory markers in serum. The highest incidence of peaks at BL was found for interferon γ (37.5% of the periodontitis subjects). For the four biomarkers with a detection frequency of >75% at BL (IL-1ra, IL-8, macrophage inflammatory protein 1ß, and vascular endothelial growth factor), no significant difference was observed over time for the P group or between the two groups at BL. The significant correlation found between the serum and the GCF for certain cytokines and the fact that periodontitis subjects exhibit high peaks for several inflammatory markers in serum may support the hypothesis that the inflammatory reaction due to periodontitis is not restricted to the diseased sites. Within the limitations of the study, periodontal therapy did not seem to have any significant impact on the systemic cytokine levels.

Metabolomics and Cytokine Analysis for Identification of Severe Drug-Induced Liver Injury.

AIM: To evaluate the levels of metabolites and cytokines in the serum of patients with severe and non-severe idiosyncratic drug-induced liver injury (DILI) and to identify biomarkers of DILI severity. METHODS: Gas chromatography-mass spectrometry (GC-MS) and ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) based metabolomic approaches were used to evaluate the metabolome of serum samples from 29 DILI patients of severity grade 3 (non-severe), 27 of severity grade 4 (severe), and 36 healthy control (HC). The levels of total keratin-18 (K18), fragment K18, and 27 cytokines were determined by enzyme-linked immunosorbent assay. RESULTS: The alkaline phosphatase activity ( p = 0.021) and international normalized ratio (INR) ( p < 0.001) differed significantly between the severe and non-severe groups. The severe group had a higher serum fragment K18 level than the non-severe group. A multivariate analysis showed good separation between all pairs of the HC, non-severe, and severe groups. According to the orthogonal partial least-squares-discriminant analysis (OPLS-DA) model, 14 metabolites were selected by GC-MS and 17 by UPLC-MS. Among these metabolites, the levels of 16 were increased and of 15 were decreased in the severe group. A pathway analysis revealed major changes in the primary bile acid biosynthesis and alpha-linolenic acid metabolic pathways. The levels of PDGF-bb, IP-10, IL-1Rα, MIP-1ß, and TNF-α differed significantly between the severe and non-severe groups, and the levels of most of the metabolites were negatively correlated with those of these cytokines. An OPLS-DA model that included the detected metabolites and cytokines revealed clear separation of the severe and non-severe groups. CONCLUSION: We identified 31 metabolites and 5 cytokines related to the severity of idiosyncratic DILI. The primary bile acid biosynthesis and alpha-linolenic acid metabolism pathways were also related to the severity of DILI. A model that incorporated the metabolites and cytokines showed clear separation between patients with severe and non-severe DILI, suggesting that these biomarkers have potential as indicators of DILI severity.

Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5.

Mesenchymal stem cells (MSCs) are recruited from BM to the stroma of developing tumors, where they serve as critical components of the tumor microenvironment by secreting growth factors, cytokines, and chemokines. The role of MSCs in colorectal cancer (CRC) progression was controversial. In this study, we found that C-C chemokine receptor type 5 (CCR5) ligands (i.e., C-C motif chemokine ligand 3 (CCL3), CCL4, and CCL5) were highly produced from MSCs using a chemokine array screening with conditioned media from the cultured human MSCs. A relatively strong CCR5 expression could be detected within the cytoplasm of several CRC cell lines. Regarding the effect of MSC, we found that the xenografts in which CCR5-overexpressing HCT116 cells were inoculated into immunocompromised mice were highly promoted in vivo by a mixture with MSCs. Notably, the CCR5 inhibitor, maraviroc, significantly abolished the MSC-induced tumor growth in vivo. In human clinical specimens (n = 89), 20 cases (29%) were high for CCR5, whereas 69 cases (71%) were low. Statistical analyses indicated that CCR5 expression in primary CRC was associated with CRC patients' prognosis. Especially, stage III/IV patients with CCR5-high CRCs exhibited a significantly poorer prognosis than those with CCR5-low CRCs. Furthermore, we investigated the effects of preoperative serum CCR5 ligands on patients' prognosis (n = 114), and found that CRC patients with high serum levels of CCL3 and CCL4 exhibited a poorer prognosis compared to those with low levels of CCL3 and CCL4, while there was no association between CCL5 and prognosis. These results suggest that the inhibition of MSC-CRC interaction by a CCR5 inhibitor could provide the possibility of a novel therapeutic strategy for CRC, and that serum levels of CCL3 and CCL4 could be predictive biomarkers for the prognosis of CRC patients.

Human NK cells adapt their immune response towards increasing multiplicities of infection of Aspergillus fumigatus.

BACKGROUND: The saprophytic fungus Aspergillus fumigatus reproduces by generation of conidia, which are spread by airflow throughout nature. Since humans are inhaling certain amounts of spores every day, the (innate) immune system is constantly challenged. Even though macrophages and neutrophils carry the main burden, also NK cells are regarded to contribute to the antifungal immune response. While NK cells reveal a low frequency, expression and release of immunomodulatory molecules seem to be a natural way of their involvement. RESULTS: In this study we show, that NK cells secrete chemokines such as CCL3/MIP-1α, CCL4/MIP-1ß and CCL5/RANTES early on after stimulation with Aspergillus fumigatus and, in addition, adjust the concentration of chemokines released to the multiplicity of infection of Aspergillus fumigatus. CONCLUSIONS: These results further corroborate the relevance of NK cells within the antifungal immune response, which is regarded to be more and more important in the development and outcome of invasive aspergillosis in immunocompromised patients after hematopoietic stem cell transplantation. Additionally, the correlation between the multiplicity of infection and the expression and release of chemokines shown here may be useful in further studies for the quantification and/or surveillance of the NK cell involvement in antifungal immune responses.

Differential chemokine expression under the control of peripheral blood mononuclear cells issued from Alzheimer's patients in a human blood brain barrier model.

Growing evidence highlights the peripheral blood mononuclear cells (PBMCs) role and the chemokine involvement in the Alzheimer's disease (AD) physiopathology. However, few data are available about the impact of AD PBMCs in the chemokine signature in a brain with AD phenotype. Therefore, this study analyzed the chemokine levels in a human blood brain barrier model. A human endothelial cell line from the immortalized cerebral microvascular endothelial cell line (hCMEC/D3) and a human glioblastoma U-87 MG cell line, both with no AD phenotype were used while PBMCs came from AD at mild or moderate stage and control patients. PBMCs from moderate AD patients decreased CCL2 and CCL5 levels in endothelial, and also CXCL10 in abluminal compartments and in PBMCs compared to PBMCs from mild AD patients. The CX3CL1 expression increased in endothelial and abluminal compartments with PBMCs from mild AD patients compared to controls. AD PBMCs can convert the chemokine signature towards that found in AD brain, targeting some chemokines as new biomarkers in AD.

Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults.

OBJECTIVES: Chronic stress is associated with poorer age-related cognition, but the mechanisms of this relationship are not well understood. Aging increases expression of activated macrophages, leading to exacerbated immune responses to stressors. We examined the impact of stress and aging on macrophage-related inflammation and cognition in clinically normal adults. METHODS: Three hundred eighty clinically normal adults were followed longitudinally (age M = 73 years; visit range: 1-8; M = 2.5 visits). Participants completed the Perceived Stress Scale, a neuropsychological battery, and blood draws. Plasma was analyzed for cytokines related to macrophage function (interleukin 6, tumor necrosis factor alpha, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). Linear mixed-effects examined the effects of age, baseline stress, and their interaction predicting macrophage cytokines, adjusting for sex, education, and depressive symptoms. Latent growth curve models assessed the mediating role of macrophage cytokines in the relationship between age and cognition in high or low stress. RESULTS: Baseline perceived stress interacted with age to predict macrophage cytokines longitudinally. Specifically, high-stress adults demonstrated accelerated age-related elevations in macrophage cytokines across time. Macrophage cytokines negatively tracked with executive functioning longitudinally. Macrophage cytokines mediated 19% of the relationship between age and executive function in high-stress, but not low-stress, adults. CONCLUSIONS: Our data provide evidence of accelerated immune aging among individuals with high stress. Elevated macrophage cytokine trajectories mediated the effect of age on executive function only in individuals with high stress, suggesting these constructs may be more tightly linked in elevated stress contexts. Stress interventions are warranted to optimize immune aging, with possible downstream cognitive benefits among even clinically normal adults.

Eotaxin­1 and MCP­1 serve as circulating indicators in response to power frequency electromagnetic field exposure in mice.

The increasing public concern regarding the potential health risks of exposure to electromagnetic fields (EMFs) has led to intensive research in this area. However, it remains unclear whether potential pro­oncogenic effects may be caused by power frequency EMF (PFEMF) exposure. To address the associated risk factors, the present study exposed 4­week old Balb/c mice to 0, 0.1, 0.5 and 2.5 mT of constant 50 Hz Helmholtz coil­type PFEMF for 90 days to explore the circulating chemokine indicators that may be associated with inflammation or cancer. No measurable weight difference existed between the control and PFEMF­exposure groups; however, the Luminex assay clearly demonstrated differentially responsive profiles of circulating chemokines upon PFEMF treatment. Monocyte chemoattractant protein (MCP)­3, macrophage inflammatory protein (MIP)­1α, MIP­1ß and MIP­2 levels in serum were not significantly altered by PFEMF during the 3­month exposure period; however, the circulating levels of other chemokines including IP­10, GROα, RANTES, EOTAXIN­1 and MCP­1 exhibited significant changes upon treatment. Among the responsive chemokines, EOTAXIN­1 and MCP­1 were significantly increased by 0.5 mT of PFEMF treatment, which may support their use as indicators of PFEMF exposure. This novel finding highlights the potential pro­inflammatory nature of power frequency, which may shed light on the mechanisms underlying PFEMF­induced diseases, including cancer.

SNPs in inflammatory genes CCL11, CCL4 and MEFV in a fibromyalgia family study.

BACKGROUND: Fibromyalgia (FM) is a chronic pain syndrome with a high incidence in females that may involve activation of the immune system. We performed exome sequencing on chemokine genes in a region of chromosome 17 identified in a genome-wide family association study. METHODS AND FINDINGS: Exome sequence analysis of 100 FM probands was performed at 17p13.3-q25 followed by functional analysis of SNPs found in the chemokine gene locus. Missense SNPs (413) in 17p13.3-q25 were observed in at least 10 probands. SNPs rs1129844 in CCL11 and rs1719152 in CCL4 were associated with elevated plasma chemokine levels in FM. In a transmission disequilibrium test (TDT), rs1129844 was unequally transmitted from parents to their affected children (p< 0.0074), while the CCL4 SNP was not. The amino acid change (Ala23Thr), resulting from rs1129844 in CCL11, predicted to alter processing of the signal peptide, led to reduced expression of CCL11. The variant protein from CCL4 rs1719152 exhibited protein aggregation and a potent down-regulation of its cognate receptor CCR5, a receptor associated with hypotensive effects. Treatment of skeletal muscle cells with CCL11 produced high levels of CCL4 suggesting CCL11 regulates CCL4 in muscle. The immune association of FM with SNPs in MEFV, a chromosome 16 gene associated with recurrent fevers, had a p< 0.008 TDT for a combined 220 trios. CONCLUSIONS: SNPs with significant TDTs were found in 36% of the cohort for CCL11 and 12% for MEFV, along with a protein variant in CCL4 (41%) that affects CCR5 down-regulation, supporting an immune involvement for FM.

Decreased macrophage inflammatory protein (MIP)-1α and MIP-1ß increase the risk of developing nasopharyngeal carcinoma.

BACKGROUND: The association of circulating inflammation markers with nasopharyngeal carcinoma (NPC) is still largely unclear. This study aimed to comprehensively explore the relationship between circulating cytokine levels and the subsequent risk of NPC with a two-stage epidemiologic study in southern China. METHODS: The serum levels of 33 inflammatory cytokines were first measured in a hospital-based case-control study (150 NPC patients and 150 controls) using multiplex assay platforms. Marker levels were categorized into two or more groups based on the proportion of sample measurements that was above the lower limit of detection. Odds ratios (ORs) and 95% confidence intervals (CIs) relating the serum marker concentration to the risk of NPC were computed by multivariable logistic regression models. The associations were validated in 60 patients with NPC and 120 controls in a subsequent nested case-control study within a NPC screening trial. Potential interactions between serum cytokines and Epstein-Barr virus (EBV) relating to the risk of NPC were assessed using a likelihood ratio test. RESULTS: The levels of serum macrophage inflammatory protein (MIP)-1α and MIP-1ß in the highest categories were associated with a decreased risk of NPC in both the case-control study (MIP-1α: OR = 0.49, 95% CI = 0.26-0.95; MIP-1ß: OR = 0.47, 95% CI = 0.22-1.00) and the nested case-control study (MIP-1α: OR = 0.13, 95% CI = 0.03-0.62; MIP-1ß: OR = 0.20, 95% CI = 0.04-0.94), compared with those in the lowest categories. Furthermore, individuals with lower levels of these two cytokine markers who were EBV seropositive presented with a largely higher risk of NPC compared with patients with higher levels who were EBV seronegative in both the case-control study (MIP-1α: OR = 16.28, 95% CI = 7.11-37.23; MIP-1ß: OR = 12.86, 95% CI = 5.9-28.05) and the nested case-control study (MIP-1α: OR = 86.12, 95% CI = 10.58-701.03; MIP-1ß: OR = 115.44, 95% CI = 13.92-957.73). CONCLUSIONS: Decreased preclinical MIP-1α and MIP-1ß levels might be associated with a subsequently increased risk of NPC. More mechanistic studies are required to fully understand this finding.