Cutaneous T-cell-attracting Chemokine Research Articles

Investigating the effects of cytokine biomarkers on HIV incidence: a case study for individuals randomized to pre-exposure prophylaxis vs. control.

Understanding and identifying the immunological markers and clinical information linked with HIV acquisition is crucial for effectively implementing Pre-Exposure Prophylaxis (PrEP) to prevent HIV acquisition. Prior analysis on HIV incidence outcomes have predominantly employed proportional hazards (PH) models, adjusting solely for baseline covariates. Therefore, models that integrate cytokine biomarkers, particularly as time-varying covariates, are sorely needed. We built a simple model using the Cox PH to investigate the impact of specific cytokine profiles in predicting the overall HIV incidence. Further, Kaplan-Meier curves were used to compare HIV incidence rates between the treatment and placebo groups while assessing the overall treatment effectiveness. Utilizing stepwise regression, we developed a series of Cox PH models to analyze 48 longitudinally measured cytokine profiles. We considered three kinds of effects in the cytokine profile measurements: average, difference, and time-dependent covariate. These effects were combined with baseline covariates to explore their influence on predictors of HIV incidence. Comparing the predictive performance of the Cox PH models developed using the AIC metric, model 4 (Cox PH model with time-dependent cytokine) outperformed the others. The results indicated that the cytokines, interleukin (IL-2, IL-3, IL-5, IL-10, IL-16, IL-12P70, and IL-17 alpha), stem cell factor (SCF), beta nerve growth factor (B-NGF), tumor necrosis factor alpha (TNF-A), interferon (IFN) alpha-2, serum stem cell growth factor (SCG)-beta, platelet-derived growth factor (PDGF)-BB, granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and cutaneous T-cell-attracting chemokine (CTACK) were significantly associated with HIV incidence. Baseline predictors significantly associated with HIV incidence when considering cytokine effects included: age of oldest sex partner, age at enrollment, salary, years with a stable partner, sex partner having any other sex partner, husband's income, other income source, age at debut, years lived in Durban, and sex in the last 30 days. Overall, the inclusion of cytokine effects enhanced the predictive performance of the models, and the PrEP group exhibited reduced HIV incidences compared to the placebo group.

Mapping the causal associations of cytokines with sarcopenia and aging traits: Evidence from bidirectional Mendelian randomization.

Cytokines and growth factors may serve as a bridge in studying the causal relationships between inflammaging and sarcopenia due to their roles in inflammaging. In this study, we aim to explore the causal association of cytokines with sarcopenia and aging traits and further identify the significant inflammation factors. Bidirectional Mendelian randomization (MR) analysis was used to identify the causality. Forty-one kinds of circulation cytokines and growth factors were set as exposures, and the data were from a summary genome-wide association study (GWAS) containing three cohorts with 8293 healthy participants of European ancestry from 1983 to 2011. Hand grip strength, adjusted appendicular lean mass (AALM), usual walking pace, moderate-to-vigorous physical activity (MVPA) levels, able to walk or cycle unaided for 10min (AWCU10) and telomere length were selected as outcomes. Data for outcomes were obtained from meta-GWAS and the UK Biobank, and sample sizes ranged from 69537 to 472174. Low hand grip strength was defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and Foundation for the National Institutes of Health (FNIH) cut-off points, respectively. Other outcome traits were defined and measured according to the UK Biobank and raw cohorts' criteria. We set two significance thresholds for single nucleotide polymorphisms (SNPs) associated with exposures to obtain adequate SNPs (5×10-6 and 5×10-8). Inverse-variance weighted, MR-Egger and weighted median were employed to estimate the causality. Twenty-seven factors were identified to relate to sarcopenia and aging traits causally, and most were associated with only one outcome trait. IL16 (interleukin-16), CTACK (cutaneous T-cell attracting chemokine), MIP1b (macrophage inflammatory protein 1b) and PDGFbb (platelet-derived growth factor BB) were proven to relate causally to at least one sarcopenia and aging trait in both analyses with two significance thresholds. IL16 was causally associated with hand grip strength (0.977 [0.956-0.998] for EWGSOP and 0.933 [0.874-0.996] for FNIH), AALM (0.991 [0.984, 0.998]), MVPA (0.997 [0.995-1.000]) and AWCU10 (1.008 [1.003-1.013]). CTACK was proven to relate causally to hand grip strength (1.013 [1.007-1.019] for EWGSOP and 1.090 [1.041-1.142] for FNIH), AWCU10 (0.990 [0.986-0.994]) and telomere length (0.998 [0.983-0.994]). The results indicated that MIP1b has a causal effect on hand grip strength (1.032 [1.001-1.063] for EWGSOP), AWCU10 (0.994 [0.988-1.000] and 0.993 [0.988-0.998]) and telomere length (1.006 [1.000-1.012]). PDGFbb may causally relate to AALM (1.016 [1.001-1.030]) and telomere length (1.011 [1.007-1.015]). Reserve MR analyses also proved their unidirectional causal effects. Twenty-seven factors were causally related to sarcopenia and aging traits, and the causal effects of IL16, CTACK, MIP1b and PDGFbb were proven in both analyses with two significance thresholds.

Causal relationship between circulating inflammatory factors and osteoporosis: a bidirectional Mendelian randomization study.

Osteoporosis (OP), a persistent metabolic bone disorder linked with inflammation, has an undetermined cause. In our research, we employed bidirectional Mendelian randomization (MR) to investigate the interplay between OP and inflammation agents. We performed two-way pooled-level MR analyses to characterize the causal relationship between 41 circulating inflammatory modulators and OP. Genetic variation data for the 41 regulatory factors associated with inflammation were obtained from genome-wide association studies (GWASs) of human cytokines. Bone mineral density (BMD) was utilized as a phenotype for OP in our approach. The BMD dataset, sourced from the GEFOS consortium, a large GWAS meta-analysis study and UK Biobank, was classified based on varied sections [whole body (TB), lumbar spine (LS), femoral neck (FN), forearm (FA), and heel] and age brackets (0-15 years, 15-30 years, 30-45 years, 45-60 years, and above 60 years). Primary MR analyses were executed using the inverse variance weighting (IVW) method, and sensitivity analyses were performed using the MR-Egger, weighted median, simple model, and weighted model. Cochran's Q test was utilized to evaluate the existence of heterogeneity. We used MR-Egger regression and MR multiplicity of residuals and outliers (MR-PRESSO) to assess pleiotropy. After false discovery rate (FDR) correction, elevated levels of circulating interleukin-8 (IL-8) [β = 0.072 (0.031-0.114), p < 0.01], macrophage inflammatory protein-1b (MIP-1β) [β = 0.008 (0.003-0.013), p < 0.01; β = 0.026 (0.009-0.042), p < 0.01], and cutaneous T-cell attracting chemokine (CTACK) [β = 0.037 (0.017-0.056), p < 0.01] was associated with a reduced risk of OP. Reduced levels of hepatocyte growth factor (HGF), IL-1ra, IL-10, macrophage colony-stimulating factor (MCSF), and MIP-1α were associated with a reduced risk of OP [β = -0.030 (-0.047 - -0.013), p < 0.01; β = -0.025 (-0.041 - -0.010), p < 0.01; β = -0.018 (-0.029 - -0.007), p < 0.01; β = -0.060 (-0.097 - -0.024), p < 0.01; β = -0.118 (-0.190 - -0.047), p < 0.01]. We observed a significant causal correlation between FN-BMD and MCP-3 (FDR < 0.05). The occurrence of OP may also lead to elevated levels of MCP3 [β = -0.466 (-0.714 - -0.217), p < 0.01]. The reliability of the results was confirmed by sensitivity analyses. This study demonstrated the pathogenic role of circulating inflammatory modulators in OP using bidirectional MR analysis. This further deepens the understanding of OP pathogenesis and provides new ideas for therapeutic intervention in OP.

Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study

ObjectiveTo investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). MethodsWe performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. ResultsIn total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. ConclusionCP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.

Potential biomarkers of atopic dermatitis.

Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disease with a wide range of heterogeneity. Accurate biomarkers or predictors are the keys to instructing personalized tailored precise treatment. The development of technology such as transcriptomics, genomics, and proteomics provides novel insights into the possibility to find potential biomarkers. Meanwhile, emerging minimally invasive methods such as tape stripping were used to reveal different profiles of patients' skin without biopsy. Several potential biomarkers or predictors have been found. In this review, we summarized the current development of potential biomarkers of AD. Nitric oxide synthase 2/inducible nitric oxide synthase (NOS2/iNOS), human beta-defensin-2 (hBD-2), and matrix metalloproteinases 8/9 (MMP8/9) may be the candidate biomarkers for AD diagnosis. Filaggrin (FLG) gene mutation increased the occurrence risk of AD. Fatty-acid-binding protein 5 (FABP5) may serve as an effective biomarker for the atopic march (AM). Squamous cell carcinoma antigen 2 (SCCA2), serum thymus and activation-regulated chemokine (TARC), cutaneous T-cell-attracting chemokine (CTACK), eosinophil-derived neurotoxin (EDN), macrophage-derived chemokine (MDC), lactate dehydrogenase (LDH), and interleukin (IL)-18 can be the candidate biomarkers for disease severity monitoring. IL-17, IL-23, IL-33, and indoleamine 2,3-dioxygenase (IDO1) can be used as predictive biomarkers for AD comorbidities. LDH, TARC, pulmonary and activation-regulated chemokine (PARC), periostin, IL-22, eotaxin-1/3, and IL-8 may be the candidate biomarkers for monitoring treatment effects. There are still unmet needs and a long way to go for more convenient, non-invasive, and effective predictors and biomarkers to better guide personalized precise treatment.

Genetically Predicted Circulating Levels of Cytokines and the Risk of Cancer.

BackgroundInflammation plays a pivotal role in the pathogenesis of cancer. Though previous studies have reported a link between several inflammatory biomarkers and risk of certain types of cancer, there is a lack of systematic investigation. Therefore, we aimed to assess the role of circulating cytokines on the risk of cancer using a two-sample Mendelian randomization (MR) approach.MethodWe used genetic variants associated with circulating levels of cytokines from a meta-analysis of genome-wide association studies (GWASs) of 8,293 Finns as instrumental variables. Summary level data of 20 site-specific cancer were obtained from the UK BioBank including up to 456,348 participants of European ancestry. We performed two-sample MR analyses using inverse-variance weighted (IVW) method as the main method, followed by weighted-median and likelihood-based methods as sensitivity analysis. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test.Results224 genetic variants associated with 27 circulating cytokines achieving genome-wide significance (P<5×10-8) were used as IVs. After Bonferroni correction, genetically predicted high levels of interleukin-18 (IL-18) were associated with a decreased risk of acute myeloid leukemia (odds ratio (OR) per 1 standard deviation (SD) increase = 0.55, 95% confidence interval (CI):0.43-0.69, P=5.39×10-7), and circulating levels of IL-17 were associated with altered stomach cancer risk (OR per 1 SD increase = 0.15, 95% CI: 0.07-0.36, P=1.25×10-5) by IVW. Results were stable across sensitivity analyses, and MR-Egger regression did not suggest the presence of directional pleiotropy. Additionally, we found suggestive evidence for 48 cytokine-cancer associations including tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and cutaneous T-cell attracting chemokine (CTACK) with the risk of several types of cancer (9.26×10-5≤P<0.05).ConclusionsBy using a genetic epidemiological approach, our study systematically evaluated the role of circulating cytokines on the risk of cancer, and provided clues for potential therapeutic targets. However, the exact underlying biological mechanism warrants further investigation.

The role of cutaneous T-cell attracting chemokine in the development of different phenotypes of atopic dermatitis in children

The goal of this study was to detect the risk of developing different atopic dermatitis (AD) phenotypes in children (isolated or combined with other comorbid atopic diseases (AtD)) depending on serum concentrations of cutaneous T-cell attracting chemokine (CTACK)/CCL27. The main group comprised 39 children aged 3 to 18 years old suffering from different AD phenotypes – isolated (18 patients) and combined with comorbid AtD – AR/ARC and/or bronchial asthma (21 patients). The control group comprised 47 children aged 3 to 18 years old, suffering from diseases of the gastrointestinal tract (GIT). Serum CTACK/CCL 27 concentrations were detected in all children. In the full main group, the average level of CTACK/CCL27 was significantly higher compared to the patients of the control group: 4403.6 pg/ml (95% CI: 3726.2; 5148.7, p&lt;0.001) and 3495.9 pg/ml (95% CI: 3197.8; 4186.8, p&lt;0.001), respectively. Mean serum CTACK/CCL27 levels in patients of the main group with different AD phenotypes were higher than those in the full main group: with isolated AD – 4549.4 pg/ml (LQ; HQ: 3923.5; 5175.2, p&lt;0.05), with AD associated with other AtD – 5116.6 pg/ml (LQ, HQ: 4062.8; 6170.5, p&lt;0.05). In phenotypes of overall and isolated AD, the cut-off value of serum CTACK/ CCL27 is 3586.5 pg/ml (76.9% and 77.8%, respectively, and 38.3% in the control group). The risk of development at this concentration is 5.37 (95% CI: 2.05; 14.07, p&lt;0.001) for the total AD phenotype and 5.64 (95% 1.56; 20.32, p&lt;0.05) for the isolated AD phenotype. In AD phenotype combined with comorbid AtD, the cut-off value of serum CTACK/CCL27 is 4308.8 pg/ml (66.7% of the main and 21.3% in the control group). The risk of developing this AD phenotype at this concentration is 7.40 (95% CI: 2.30; 23.76, p&lt;0.001). Serum CTACK/CCL27 levels are the reliable biomarker of the risk for developing different AD phenotypes in children. In the serum level of CTACK/CCL27=3658.5 pg/ml, the significant risk of developing total AD phenotype is 5.37, and isolated – AD=5.64. In the serum concentration of CTACK/CCL27=4308.8 pg/ml, the significant risk of developing AD phenotype combined with comorbid AtD is 7.40.

Cutaneous T-cell-attracting chemokine as a novel biomarker for predicting prognosis of idiopathic pulmonary fibrosis: a prospective observational study

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients.MethodsA multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed.ResultsIn the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01–1.07; IL-8, HR = 1.04, 95% CI 1.01–1.08; MIP-1α, HR = 1.19, 95% CI 1.00–1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02–1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01–1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls.ConclusionsCTACK is a novel prognostic biomarker of IPF.Trial registration None (because of no healthcare intervention)

Distinct circulating cytokine levels in patients with angiography-proven coronary artery disease compared to disease-free controls

Abstract Background Systemic inflammation has a critical role in the development of coronary artery disease (CAD). Identification of inflammatory pathways may provide a platform for novel therapeutic approaches. Purpose We sought to determine whether there are differences in circulating cytokine profiles between patients with CAD and disease-free controls. Methods Study population consisted of 458 patients who underwent diagnostic invasive coronary angiography for clinical indications. Altogether 312 patients had angiographically significant CAD whereas 146 had no angiographically-detected coronary atherosclerosis. We measured the serum concentrations of 48 circulating cytokines. Results Patients with CAD had increased levels of interleukin-1 receptor antagonist (IL-1-RA), interleukin-2 receptor alpha (IL-2Rα), IL-3, IL-4, IL-6, IL-9, IL-10, IL-16, IL-17, IL-18, granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor-BB (PDGF-BB), macrophage inflammatory protein-1-beta (MIP-1-β), tumor necrosis factor-alpha (TNF-α), TNF-β, cutaneous T-cell-attracting chemokine (CTACK), growth regulated oncogene alpha (GRO-α), hepatocyte growth factor (HGF), interferon alpha-2 (IFNα-2), leukemia inhibitory factor (LIF), macrophage colony-stimulating factor (M-CSF), macrophage migration inhibitory factor (MIF), monokine induced by gamma interferon (MIG), beta-nerve growth factor (β-NGF), stem cell factor (SCF) and stromal cell-derived factor 1 alfa (SDF1α). On a logistic multivariate regression model adjusted with age, sex, hypertension and treatment for diabetes, increased levels of IL-4 (p=0.027, OR 1.090), IL-9 (p=0.000, OR 1.013), IL-17 (p=0.011, OR 1.005), CTACK (p=0.008, OR 1.001), MIP-1-β (p=0.004, OR 1.006), GRO-α (p=0.008, OR 1.004), TNF-α (p=0.019, OR 1.011) were independently associated with atherosclerosis. Conclusions Patients with CAD have distinct circulating cytokine profiles compared to disease-free controls. Based on these findings, certain cytokines may have a pivotal role in the development of atherosclerotic cardiovascular disease and cytokine-mediated pathway appear as a promising target for cardiovascular drug development. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Finnish Medical Foundation, Helsinki, Finland; The Finnish Foundation for Cardiovascular Research, Helsinki, Finland

염증성 사이토카인의 발현 억제를 통한 홍해삼 추출물의 항염증효과 및 아토피 개선효과

The red sea cucumber (RSC), Apostichopus japonicus, is a species of sea cucumber in the family Stichopodidae. It is widely distributed in China, Japan and Korea. Tumor necrosis factor-α (TNF-α) and Interferon (IFN-γ) induce inflammatory cytokines such as Thymus and activation-regulated chemokine (TARC/CCL17), Cutaneous T-cellattracting chemokine (CTACK/CCL27), interleukin-1β (IL-1β), IL-6 and IL-8. These cytokines are increased in atopic dermatitis condition. In this study, we investigated the antiinflammatory and skin regeneration effects by RCS. To investigate cytotoxic effects in HaCaT cells, we performed MTT assay after treatment with RSC extracted by 70% EtOH. As a result, RSC extracts did not have cytotoxic effect in HaCaT cells. Also, mRNA expression levels of CCL17, CCL27, IL-β, IL-6 and IL-8 genes induced by TNF-α/IFN-γ were decreased by RSC extracts. Moreover, we confirmed the release of CCL17 and CCL27 protein through ELISA assay. Wound healing assay and cell cycle assay were performed to identify cell regeneration effect of RSC extracts. These results demonstrated the prevention and treatment effects of RSC on skin inflammatory diseases such as atopic dermatitis.

Abstract 214: Immune Response Biomarkers Characterize Endothelial Injury and Predict Acute Coronary Syndrome

Acute Coronary Syndromes (ACS) are caused by free-radical mediated endothelial injury. Soft unstable coronary artery wall lesions form that can rupture causing thrombosis and obstruction. Three software systems (Akaike, Bayesian, Drop-in Deviance) tested 45 biomarkers and global risk factors to predict risk of ACS. A novel 9 protein algorithm was developed in 3 unique longitudinal, outcome-based studies and independently verified in MESA (Multiethnic Study of Atherosclerosis). The proteins selected include CTACK (Cutaneous T-Cell Attracting Chemokine)-homing of memory t-cells to tissue injury site; EOTAXIN (Eosinophil Chemotactic Protein)-attracts eosinophils to endothelial injury facilitating fibrin removal; MCP-3 (Monocyte Chemotactic Protein 3)-attracts monocytes and modulates activity; IL-16 (cytokine)-chemoattractant and modulator of T cell activation; sFAS (soluble FAS Ligand)-suppresses apoptosis; FAS Ligand (transmembrane protein tumor necrosis factor family member) induces apoptosis; HGF (Hepatocyte Growth Factor)-acts on epithelial cells and endothelial cells for angiogenesis, tumorogenesis, and tissue regeneration/repair; HDL (High-density Lipoprotein)-reverse cholesterol transport and inhibits oxidation, inflammation, endothelial activation, coagulation, and platelet aggregation; HbA1c (Hemoglobin A1c)-three-month average plasma glucose concentration. We conclude that the selection of biomarkers associated with endothelial damage and immune system response correlates with risk of ACS and reflects the underlying pathophysiology. Further studies are warranted.

Biomarkers for atopic dermatitis: a systematic review and meta-analysis.

A large number of studies investigating the correlation between severity of atopic dermatitis and various biomarkers have been published over the past decades. The aim of this review was to identify, evaluate and synthesize the evidence examining the correlation of biomarkers with disease severity in atopic dermatitis patients, something that has not been performed previously. Three electronic databases were systematically searched and relevant studies were selected for inclusion. A total of 222 articles, reporting on 115 different biomarkers in 30 063 patients, were critically appraised. Studies were divided into two main groups. The first group consisted of longitudinal randomized controlled trials and cohort studies, which reported measurements at multiple time points. The second contained cross-sectional studies that reported only one measurement per patient. Out of 222 articles, 108 articles reported sufficient data for meta-analysis. Only four biomarkers were eligible for meta-analysis in the longitudinal group, and nine in the cross-sectional group. Serum thymus and activation-regulated chemokine (TARC) was found to be the most reliable biomarker studied, showing pooled correlation coefficients of 0.60 (95% CI 0.48-0.70) and 0.64 (95% CI 0.57-0.70) in longitudinal and cross-sectional studies, respectively. Additional biomarkers that could prove useful but require additional research include serum cutaneous T-cell attracting chemokine (CTACK), sE-selectin, macrophage-derived chemokine (MDC), lactate dehydrogenase (LDH) and interleukin (IL)-18.

Chemokine expression in diverse nonimmediate drug hypersensitivity reactions: focus on thymus activation-regulated chemokine, cutaneous T-cell–attracting chemokine, and interleukin-10

BackgroundSkin infiltration of different types of T lymphocytes is responsible for inflammatory profiles of nonimmediate drug hypersensitivity reactions (niDHRs). Important chemokines attracting skin-specific homing T cells include thymus activation-regulated chemokine (TARC) and cutaneous T-cell–attracting chemokine (CTACK). Interleukin-10 (IL-10) is a potent chemokine attracting CD8+ T cells. ObjectiveTo investigate serum levels of TARC, CTACK, and IL-10 in patients with niDHRs and evaluate the correlation among these 3 chemokines. MethodsForty patients, including 19 patients with Stevens-Johnson syndrome and toxic epidermal necrolysis and 21 patients with maculopapular exanthema, and 21 healthy donors were recruited into the study. Clinical data of patients were obtained. Serum TARC, CTACK, and IL-10 levels were determined by enzyme-linked immunosorbent assay. ResultsSerum levels of TARC, CTACK, and IL-10 were significantly elevated in patients with niDHRs compared with those in normal controls (P < .05, P < .001, P < .001, respectively). The CTACK and IL-10 levels were significantly higher (P < .05, P < .001) in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis than in normal controls. Patients with maculopapular exanthema exhibited higher levels of TARC, CTACK, and IL-10 compared with normal controls (P < .001, P < .001, P < .05). Serum CTACK levels were positively correlated with TARC levels in all 40 patients (rs = 0.3422, P < .05). Serum CTACK levels positively correlated with detachment of body surface area in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis (rs = 0.510, P < .05). ConclusionThese results support a role for TARC, CTACK, and IL-10 in the pathogenesis of niDHRs for their chemotactic ability to attract different T-cell subtypes and different functional severities in niDHRs.

179 The Role Of Microparticles in Carotid Disease

IntroductionEndothelial microparticles (EMPs) are released from dysfunctional endothelial cells. We hypothesised that patients with unstable carotid plaque have higher levels of circulating microparticles compared to patients with stable plaques which...

Differential serum protein markers and the clinical severity of asthma.

BackgroundAsthma is a heterogeneous disease characterized by different clinical phenotypes and the involvement of multiple inflammatory pathways. During airway inflammation, many cytokines and chemokines are released and some are detectable in the sera.ObjectiveSerum chemokines and cytokines, involved in airway inflammation in asthma patients, were investigated.MethodsA total of 191 asthma patients were classified by hierarchical cluster analysis, including the following parameters: forced expiratory volume in 1 second (FEV1), eosinophil cationic protein (ECP) serum levels, blood eosinophils, Junipers asthma symptom score, and the change in FEV1, ECP serum levels, and blood eosinophils after 3 weeks of asthma therapy. Serum proteins were measured by multiplex analysis. Receiver operating characteristic (ROC) curves were used to evaluate the validity of serum proteins for discriminating between asthma clusters.ResultsClassification of asthma patients identified one cluster with high ECP serum levels, increased blood eosinophils, low FEV1 values, and good FEV1 improvement in response to asthma therapy (n=60) and one cluster with low ECP serum levels, low numbers of blood eosinophils, higher FEV1 values, and no FEV1 improvement in response to asthma therapy (n=131). Serum interleukin (IL)-8, eotaxin, vascular endothelial growth factor (VEGF), cutaneous T-cell-attracting chemokine (CTACK), growth-related oncogene (GRO)-α, and hepatocyte growth factor (HGF) were significantly different between the two clusters of asthma patients. ROC analysis for serum proteins calculated a sensitivity of 55.9% and specificity of 75.8% for discriminating between them.ConclusionSerum cytokine and chemokine levels might be predictors for the severity of asthmatic inflammation, asthma control, and response to therapy, and therefore might be useful for treatment optimization.

Atopic dermatitis-mitigating effects of newLactobacillusstrain,Lactobacillus sakeiprobio 65 isolated from Kimchi

Atopic dermatitis (AD) is an inflammatory skin disease. Probiotics have been reported to modulate immune responses and thus are now being suggested as potential treatments for allergies. In this study, we investigated the inhibitory effects of Lactobacillus sakei probio 65 isolated from Kimchi on artificially inducing AD in NC/Nga mice. Oral administration of viable or heat-inactivated Lact. sakei probio 65 improved the condition of skin and reduced scratching frequency. Serum levels of IgE and cutaneous T-cell-attracting chemokine (CTACK) were significantly decreased by this therapy. Dead Lact. sakei probio 65 also decreased IL-4 and IL-6 serum concentrations. Moreover, both live and dead Lact. sakei probio 65 inhibited the expression of Thymus and activation-regulated chemokine and CTACK in AD-like skin lesions. The increased levels of Foxp3 expression in the lesional skin and ears were also suppressed by Lact. sakei probio 65. In addition, Lact. sakei probio 65 inhibited β-hexosaminidase release and the secretion of IL-4, TNF-α and IL-6 from RBL-2H3 cells. Oral treatment with both viable and heat-inactivated Lact. sakei probio 65 inhibits skin inflammation and AD-like skin lesions, as well as mast cell activation. Lactobacillus sakei probio 65 has an inhibitory effect on atopic dermatitis-like skin lesions and may represent an effective new anti-inflammatory agent.

Identification of Glucocorticoid-Induced TNF Receptor-Related Protein Ligand on Keratinocytes: Ligation by GITR Induces Keratinocyte Chemokine Production and Augments T-Cell Proliferation

Glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein ligand (GITRL) is a recently described co-stimulatory molecule expressed by antigen-presenting cells (APCs). Activated keratinocytes are known to engage intraepithelial T cells through co-stimulatory molecules. This study investigated the expression and function of GITRL in resting keratinocytes. We showed by immunofluorescence and flow cytometry that keratinocytes from Balb/C and C57Bl/6 mice, as well as PAM 212 murine cell line keratinocytes and human epidermal keratinocytes (HEK), express cell-surface GITRL. Stimulation of murine skin biopsies and HEK with GITR fusion protein (GITR: Fc FP) resulted in mRNA induction for chemoattractants: cutaneous T-cell-attracting chemokine (CTACK), thymus and activation-regulated chemokine (TARC), IL-8, monocyte chemoattractant protein-1 (MCP-1), and murine beta-defensin 3 (MBD3). Immunofluorescent studies on mouse biopsies treated with GITR: Fc FP confirmed corresponding TARC and MCP-1 protein production by keratinocytes. Chemokine induction was shown to be NF-kappaB-mediated. T-cell proliferation was enhanced by the addition of keratinocytes. This was reversed by pretreatment with an anti-GITRL antibody. We conclude that keratinocytes express GITRL, and that through this important co-stimulatory molecule, they have the potential to influence T-cell numbers in the skin through chemokine production and through a direct cell-cell effect on T-cell proliferation.

Short-term stress enhances cellular immunity and increases early resistance to squamous cell carcinoma

In contrast to chronic/long-term stress that suppresses/dysregulates immune function, an acute/short-term fight-or-flight stress response experienced during immune activation can enhance innate and adaptive immunity. Moderate ultraviolet-B (UV) exposure provides a non-invasive system for studying the naturalistic emergence, progression and regression of squamous cell carcinoma (SCC). Because SCC is an immunoresponsive cancer, we hypothesized that short-term stress experienced before UV exposure would enhance protective immunity and increase resistance to SCC. Control and short-term stress groups were treated identically except that the short-term stress group was restrained (2.5 h) before each of nine UV-exposure sessions (minimum erythemal dose, 3-times/week) during weeks 4–6 of the 10-week UV exposure protocol. Tumors were measured weekly, and tissue collected at weeks 7, 20, and 32. Chemokine and cytokine gene expression was quantified by real-time PCR, and CD4+ and CD8+ T cells by flow cytometry and immunohistochemistry. Compared to controls, the short-term stress group showed greater cutaneous T-cell attracting chemokine (CTACK)/CCL27, RANTES, IL-12, and IFN-γ gene expression at weeks 7, 20, and 32, higher skin infiltrating T cell numbers (weeks 7 and 20), lower tumor incidence (weeks 11–20) and fewer tumors (weeks 11–26). These results suggest that activation of short-term stress physiology increased chemokine expression and T cell trafficking and/or function during/following UV exposure, and enhanced Type 1 cytokine-driven cell-mediated immunity that is crucial for resistance to SCC. Therefore, the physiological fight-or-flight stress response and its adjuvant-like immuno-enhancing effects, may provide a novel and important mechanism for enhancing immune system mediated tumor-detection/elimination that merits further investigation.

Extracts of &lt;I&gt;Sarcoptes scabiei&lt;/I&gt; De Geer Downmodulate Secretion of IL-8 by Skin Keratinocytes and Fibroblasts and of GM-CSF by Fibroblasts in the Presence of Proinflammatory Cytokines

Previous in vitro studies showed that molecules in an extract of the mite Sarcoptes scabiei variety canis De Geer could modulate the secretion of cytokines from cultured normal human epidermal keratinocytes and dermal fibroblasts in the absence of proinflammatory cytokines in the cell culture media. The purpose of this study was to investigate whether scabies extract could also modulate cytokine and chemokine secretion from epidermal keratinocytes and dermal fibroblasts in the presence of proinflammatory cytokines that are likely present in the scabietic lesion in vivo. In particular, could the downmodulating properties of this ectoparasitic mite on skin cells be maintained in the presence of proinflammatory cytokines? We found that even in the presence of the proinflammatory cytokines interleukin (IL)-1alpha, IL-beta, and a mixture of tumor necrosis factor (TNF)alpha + IL-17, scabies extract still downregulated the levels of IL-8 secretion from keratinocytes and fibroblasts and of granulocyte/macrophage-colony stimulating factor (GM-CSF) secretion from fibroblasts that were induced by stimulation of the cells with proinflammatory cytokines alone. This study also showed that scabies molecules induced secretions of growth-related oncogene alpha (GROalpha), transforming growth factor alpha (TGFalpha), and cutaneous T-cell attracting chemokine (CTACK) from keratinocytes and IL-6 and granulocyte-colony stimulating factor (G-CSF) from fibroblasts. These findings, coupled with the previous findings that molecules in scabies extract could downregulate expression of intracellular adhesion molecule-1 (ICAM-1) and E-selectin by normal dermal microvascular endothelial cells and secretion of IL-1alpha from keratinocytes, suggest that multiple factors from scabies mites play a role in the characteristic delayed inflammatory response to a primary infestation with S. scabiei. These are adaptations that favor invasion of the host by the parasite.

CTACK/CCL27 Accelerates Skin Regeneration via Accumulation of Bone Marrow‐Derived Keratinocytes

Recent studies have suggested that bone marrow (BM) cells transdifferentiate to regenerate a variety of cellular lineages. Due to the relatively small population of BM-derived cells in each organ, it is still controversial whether these BM-derived cells are really present in sufficient numbers for effective function. Conversely, it is speculated that chemokine/chemokine receptor interactions mediate this migration of the tissue-specific precursor cells from BM into the target tissue. Here, we show that cutaneous T-cell attracting chemokine (CTACK)/CCL27 is the major regulator involved in the migration of keratinocyte precursor cells from BM into skin. By screening various chemokine expression patterns, we demonstrated that CTACK is constitutively expressed in normal skin and upregulated in wounds and that approximately 20% of CD34(+) BM cells expressed CCR10, the ligand for CTACK. Intradermal injection of CTACK/CCL27 into the periphery of skin wounds significantly enhanced BM-derived keratinocyte (BMDK) migration, and CTACK/CCL27 neutralizing antibody inhibited this BMDK migration. Furthermore, increased BMDK migration caused by CTACK/CCL27 significantly accelerated the wound-healing process without any influence over either angiogenesis or keratinocyte proliferation. These results provide direct evidence that recruitment of BM keratinocyte precursor cells to the skin is regulated by specific chemokine/chemokine receptor interactions, making possible the development of new regenerative therapeutic strategies.