Chemokine Levels In Patients Research Articles

Changes in eotaxin-3 and pulmonary and activation-regulated chemokine levels in patients after dupilumab treatment: a systematic review and meta-analysis.

Dupilumab is approved for a variety of type 2 inflammatory diseases. Changes in chemokine levels during treatment require further analysis. We evaluated changes in eotaxin-3 and PARC levels after dupilumab treatment through a meta-analysis, aiming to provide more comprehensive results. Databases were searched to select eligible publications. The study quality was assessed after inclusion. The standardized mean difference (SMD) was used for evaluation. Four studies were included. Eotaxin-3 levels were not seen significantly decreased at weeks 1 and 12, with SMD = -0.39 (95% CI: -1.78, 0.99) and -2.60 (95% CI: -5.77, 0.57), respectively (p > 0.05). Eotaxin-3 levels decreased significantly at weeks 2, 4, 8, 16, 24, 36, and 52, with SMD = -0.94 (95% CI: -1.61, -0.27); -1.17 (95% CI: -1.49, -0.84); -1.20 (95% CI: -1.52, -0.88); -1.31 (95% CI: -1.83, -0.79); -4.57 (95% CI: -6.90, -2.33); -5.28 (95% CI: -5.52, -5.04); and -4.03 (95% CI: -4.22, -3.85) (p < 0.05), respectively. PARC levels decreased significantly at weeks 4, 8, 12, and 16, with SMD = -1.08 (95% CI: -1.59, -0.58); -1.17 (95% CI: -1.68, -0.66); -1.11 (95% CI: -1.61, -0.60); and -1.15 (95% CI: -1.66, -0.64) (p < 0.05), respectively. Eotaxin-3 and PARC levels can be significantly reduced in patients treated with dupilumab.

Blood chemokine levels are markers of disease activity but not predictors of remission in early rheumatoid arthritis.

In early rheumatoid arthritis (eRA) plasma levels of specific chemokines have been shown to correlate with disease activity. However, it is unclear whether pre-treatment chemokine levels can predict disease remission at week 24, and it is not known how biological treatments with different modes of action affect plasma chemokine levels in patients with untreated eRA. This study included 347 Swedish patients with untreated eRA from the larger NORD-STAR randomised treatment trial. Here, eRA patients were treated with methotrexate combined with either prednisolone, anti-TNF (certolizumab-pegol), CTLA-4Ig (abatacept) or anti-IL6 receptor (tocilizumab). The primary clinical outcome was remission by clinical disease activity index (CDAI) defined as CDAI ≤ 2.8. Disease activity was assessed by CDAI, DAS28-ESR, DAS28-CRP, swollen joint counts, tender joint counts, ESR and CRP. The plasma concentrations of 14 chemokines were measured at baseline and after 24 weeks of treatment by bead-based immunoassay or ELISA. Baseline plasma concentrations of CXCL10, CXCL8, CXCL9, CXCL11, CXCL5 and CCL2 correlated with baseline disease activity measures. After 24 weeks of treatment, plasma levels of CXCL10, CXCL8, CXCL9, CXCL11 and CXCL13 decreased in all treatment groups except in patients treated with anti-IL6 receptor. In multivariate factor analysis, plasma chemokine levels at baseline could not differentiate patients who attained remission by week 24 from those who did not in any of the treatment groups. In patients with untreated eRA, plasma levels of several chemokines correlate with disease activity at baseline but cannot predict remission after 24 weeks of treatment with methotrexate combined with prednisolone, anti‑TNF, CTLA‑4Ig or anti‑IL6R.

CSF extracellular vesicles and risk of disease activity after a first demyelinating event

Background: Extracellular vesicles (EVs), a recently described mechanism of cell communication, are released from activated microglial cells and macrophages and are a candidate biomarker in diseases characterized by chronic inflammatory process such as multiple sclerosis (MS). Methods: We explored cerebrospinal fluid extracellular vesicle (CSF EV) of myeloid origin (MEVs), cytokine and chemokine levels in patients with clinically isolated syndrome (CIS). Results: We found that CSF MEVs were significantly higher in CIS patients than in controls and were inversely correlated to CSF CCL2 levels. MEVs level were significantly associated with an shorter time to evidence of disease activity (hazard ratio: 1.01, 95% confidence interval: 1.00–1.02, p < 0.01) independently from other known prognostic markers. Conclusion: After a first demyelinating event, CSF EVs may improve risk stratification of these patients and allow more targeted intervention strategies.

Assessment of Adipokines, CXCL16 Chemokine Levels in Patients With Rheumatoid Arthritis Combined With Metabolic Syndrome.

Objective:Rheumatoid arthritis (RA), which is a chronic systemic inflammatory disease, is associated with accelerated atherosclerosis and an increased risk of cardiovascular disease (CVD), but the causal factors have yet to be completely elucidated. The studies show that the prevalence of metabolic syndrome (MtS) was significantly higher in RA patients compared to the population. In RA and MetS inflammation and atherosclerosis are closely linked. The level of chemokines and adipokines, which may play a role in the development of atherogenesis in RA with MetS patients is currently unknown. In this study, we investigated the level of chemokine C-X-C motif chemokine ligand 16 (CXCL16) and adipokine in RA with MetS patients and assessed the association of biomarkers with clinical and biochemical activity scores of RA and components of MetS.Methods:Blood serum of 298 people (48—patients with RA and MetS, 82—with RA without MetS, 105—with MetS, 63—control group without both RA and MetS) was tested for (CXCL16), Resistin, Leptin and Fibroblast Growth Factor 21 (FGF21) levels by fluorescent antibody technique. Statistical analysis was performed using SPSS version 18.0.Results:The biomarker study showed the highest level in the RA with MetS patient group; but as compared with the RA group the differences were insignificant. CXCL16 (Me = 426.2 pg/ml (Q25-75 250.5-527.6), resistin (Me = 8685.4 pg/ml (Q25-75 6480.8-13 629.1), and FGF21 (Me = 443.6 pg/ml (Q25-75 772.9-916.3) proved to be significantly augmented in RA with MetS patients group, and in RA without MetS patients group (Me = 312.7 (Q25-75 199.4-517.7) pg/ml; Me = 8265.3 (Q25-75 5779.7-13 340.5) pg/ml; Me = 412.4 (Q25-75 300.4-497.4) pg/ml, respectively) as compared with MetS patients group (Me = 189.4 (Q25-75 130.3-280.6) pg/ml; Me = 5364.8 (Q25-75 2368.9-10 160.9) pg/ml; Me = 133.2 (Q25-75 76.2-268.6) pg/ml, respectively; P = <.001). Leptin level in all groups was higher than in the control group, but there were no differences between groups. The correlation analysis found a positive relationship between the leptin level and the waist circumference (rs = 0.39; P = .007) in the RA with MetS patients, the association of biomarkers with DAS28 score and ESR did not have any statistical significance. Conclusions: The augmented chemokine, resistin and FGF21 in the RA with MetS patients proves the systemic inflammation which is the basis of RA; the augmented leptin is linked to the abdominal obesity. These data are somewhat of an explanation of the increased risk of the CVD development in RA with MetS people. A differentiated specification can be useful to assess the cardiovascular risk of patients and justify prompt personalized treatment.

Severity of intervertebral disc herniation regulates cytokine and chemokine levels in patients with chronic radicular back pain

The contributions of intervertebral disc disease and subject-specific covariates to systemic inflammation in low back pain are unknown. We examined the effects of symptomatic disc herniation (DH) and MRI herniation severity on serum cytokine levels in clinical subjects. Cytokine levels from lumbar DH subjects (N=78) were compared to control subjects (N=57) accounting for effects of DH, age, body mass index (BMI) and gender. Effect of DH severity on cytokine levels was analyzed on subsets of subjects with acute or chronic pain. Serum cytokines were also analyzed in a subset of patients between pre- and 3 months post-surgery. Cytokine levels were elevated in the serum of patients with symptomatic DH, and the covariates age, BMI and gender significantly contributed to levels of some cytokines. Severity of herniation was a significant contributor to pain intensity (VAS), serum levels of HMGB1, PDGFbb, and IL-9. The relationship between DH severity and cytokine levels was confirmed in subjects with chronic, but not acute symptoms. Serum levels of macrophage migration inhibitory factor (MIF) decreased, whereas levels of CCL3, CCL11, CXCL1, and CXCL10 were significantly elevated post surgery. This study is the first to show that DH severity is coordinately associated with changes in serum levels of inflammatory cytokines in chronic pain subjects. HMGB1, PDGFbb and IL-9 are novel mediators of increasing DH severity, indicative of cellular damage, neuro-inflammation and angiogenesis. Resolution of inflammation was observed with decrease in MIF post surgery. However, elevated chemokine levels indicate ongoing remodeling and wound healing at 3-month time point.

Proinflammatory chemokines in the development of systemic organ-specific sensitization in infectious corneal ulcers

Purpose . The aim is to estimate the content of proinflammatory chemokines (CXCL1/GRO-α CXCL8/IL-8, CXCL10/IP-10, CXCL12/ SDF-1α, CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES, CCL11/Eotaxin) in blood serum in corneal ulcers and their relationship to the cellular immune response to corneal and uveoretinal tissues. Material and methods . 96 patients with corneal ulcer and 38 apparently healthy subjects, who made up the control group, were examined. Chemokines were determined by multiplex analysis using xMAP technology (Luminex, USA) in the xPONENT3.1 program using magnetic fluorescent microspheres and a ProcartaPlex kit (eBioscience, USA). To identify the autoimmune component, a micromodification of the leukocyte migration inhibition reaction (MIRL) with extracts of the corneal and the uveoretinal tissue of bovine eyes were used. Based on MIRL results, the patients were divided into two groups: 1 group sensitized patients (positive response to tissue antigens) — 33 (34 %) patients, 2 group — nonsensitized patients (negative response to tissue antigens) — 63 (66 %) patients. Results . The group of patients showed 2–10 times higher concentrations of the following chemokines, with respect to the control group: CXCL8/IL-8, CXCL12/SDF-1α, CXCL10/IP-10, ССL2/MCP-1, CCL4/MIP-1β, CCL5/RANTES. Shifts of CXC-chemokines (CXCL8/IL-8, CXCL12/SDF-1α, CXCL1/GRO-α, CXCL10/IP-10) in patients with central corneal ulcer were associated with increased systemic cellular immune response to eye tissue antigens; the most expressed dynamics was noted for chemokine CXCL8/IL8. Сonclusions . The revealed changes in CXC- and CC-classes chemokine levels in patients’ blood characterize the corneal ulcers an immopathologic process and validate the necessity of further research into diagnostic informativeness of the presented mediator spectrum as biological markers for the prognosis of corneal ulcers and their complications in wider clinical samples. Concentration of serum CXC chemokines, and most directly CXCL8/IL-8 can serve as an additional marker for the development of a cellular immune response to eye tissue antigens in patients with a central corneal ulcer.

Effects of Fingolimod on Cytokine and Chemokine Levels in Patients with Multiple Sclerosis (P4.2-048)

Effects of Fingolimod on Cytokine and Chemokine Levels in Patients with Multiple Sclerosis (P4.2-048)

Circulating levels of chemokines in patients with psoriasis vulgaris and their association with disease severity: A case-control study from North India.

Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and incomplete differentiation of epidermis, and accumulation of neutrophils and proinflammatory T cells in epidermis and dermis. Chemokines are believed to be the main players mediating the chemotaxis of leucocytes to the lesional site. Previous studies have established the role of various chemokine ligands and receptors at the lesional site in psoriasis. In this study, we have compared the serum levels of various chemokines, namely, inducible protein-10 (IP-10) (CXCL10), MCP-1 (CCL-2), monokine induced by gamma interferon (MIG) (CXCL-9), RANTES (CCL5), interleukin (IL)-8, and eotaxin in patients with chronic plaque psoriasis with that of healthy controls. We also studied whether the chemokine levels varied within different patient groups based on various clinical and demographic parameters, and if any of these chemokines correlated with disease activity. We studied 40 patients with chronic plaque psoriasis from a single center. Their clinical and demographic details were recorded in predesigned prforma. Patients with unstable forms of psoriasis like guttate, erythrodermic, or pustular psoriasis were excluded. The serum chemokine levels were measured by flow cytometry-based bead array set system. The serum levels of the patients were compared with that of 25 healthy controls. A subgroup analysis was also done to study the correlation of chemokine levels with age, sex, duration, and severity of disease. We observed a significant decrease in serum level of all these chemokines in patients, when compared with that of healthy controls. We also found that MIG levels showed a positive correlation with disease severity based on Psoriasis Area and Severity Index. The major limitation of the study is lack of data on the lesional chemokine levels compared to serum chemokines. The inflammatory process in psoriasis is orchestrated through chemokines. MIG is a potential serum biomarker for assessing disease severity.

Effect of thrombopoietin-receptor agonists on circulating cytokine and chemokine levels in patients with primary immune thrombocytopenia (ITP)

Background: Thrombopoietin-receptor-agonists (TPO-RAs) increase platelet production in Immune Thrombocytopenia (ITP) by stimulating Mpl. The effect of TPO-RAs on inflammatory cytokine production in ITP patients has not been well investigated. Methods: Plasma samples from 48 ITP patients treated with TPO-RAs (median age 50 years (inter-quartile range; IQR 20–69), median platelet counts 24 × 109/L (IQR 15–47 × 109/L), 28 females) and 16 healthy controls (nine females, median age 37 years, IQR 22–51 years) were collected before and during treatment, and analyzed for a panel of cytokines and chemokines by enzyme-linked immunosorbent assay and immuno-bead-based multiplex assay. Results: Elevated levels of C-X-C motif chemokine 10 (CXCL10; p < 0.001) and osteoprotegerin (OPG; p < 0.05) were observed in pretreatment samples compared to controls; these levels decreased during 6 months of treatment. Pretreatment levels of transforming growth factor (TGF)-β were lower than in healthy controls and increased after 6 months of treatment (p < 0.05). Levels of sCD40L increased after 6 months of treatment (p < 0.05), but decreased thereafter to pretreatment values. The increase in TGF-β and sCD40L may reflect increased platelet turnover. Levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-10 did not change during treatment. Conclusion: These findings suggest that treatment with TPO-RA creates a more balanced steady-state of immune activation.

Cyclophosphamide and Fludarabine Conditioning Chemotherapy Induces a Key Homeostatic Cytokine Profile in Patients Prior to CAR T Cell Therapy

This study is supported in part by funding from the Cooperative Research and Development Agreement (CRADA) between the National Cancer Institute and Kite PharmaIntroduction: CAR-engineered autologous T-cell therapy has shown promising activity in relapsed/refractory B-cell malignancies in an ongoing phase 1 study (Kochenderfer et al. J Clin Oncol 2014). Lymphodepleting conditioning chemotherapy is critical for optimal CAR T-cell activity in animal models. We evaluated the effects of conditioning chemotherapy on cytokine and chemokine levels in patients dosed with anti-CD19 CAR T cells.Methods: In this National Cancer Institute clinical trial (NCT00924326), patients with relapsed/refractory B-cell malignancies received conditioning with cyclophosphamide and fludarabine daily for 3 days starting on day -5; followed by anti-CD19 CAR T cells engineered with a CAR comprising CD28 and CD3-zeta signaling domains. Forty one cytokines, chemokines and immune response related markers were measured in the blood of patients pre (day -5) and post conditioning (day 0) by using EMD Millipore Luminex® xMAP® multiplex assays. Data acquisition and analysis were performed using a Luminex 200™ instrument and xPONENT® 3.1 data analysis software. Increases in cytokine and chemokine levels were analyzed pre- and post- conditioning, and the fold-changes in cytokine and chemokine levels were analyzed relative to clinical outcome subsequent to infusion with anti-CD19 CAR T cells. Analyses were performed with the Wilcoxon rank sum test adjusted for multiplicity with a Bonferroni correction, using a nominal level of 0.006 for significance.Results: Samples from 15patients have been evaluated. There were significant increases pre- to post-conditioning in the levels of interleukin 15 (IL-15; p=0.001), interleukin 7 (IL-7; p=0.0002), and monocyte chemoattractant protein-1 (MCP-1; p<0.0025) in blood, five days after the initiation of conditioning chemotherapy. Levels of interferon-gamma induced protein 10 (IP-10) were elevated post-conditioning, but did not meet the threshold for significance (p=0.048). Compared with baseline, levels of IL-15 increased on average 13 fold and levels of IL-7, IP-10 and MCP-1, about 2 fold. Comparison of the fold-increases in IL-15 upon conditioning between responders and non-responders approached significance (p=0.01), but did not meet the threshold after multiplicity adjustment. Larger fold-change increases for responders versus non-responders were also observed with placental growth factor (PLGF) (median fold increase 2.6 v. 1.6, average fold increase 32 v 4.2), C-reactive protein (CRP) (median fold increase 3.5 v 2.4, average fold increase 6.6 v. 2.0), IP-10 (median fold increase 2.1 v. 0.7, average fold increase 2.6 v. 2.8), and interleukin 10 (IL-10) (median fold increase 1.8 v. 0.4, average fold increase 3.1 v. 2.0), but did not meet the threshold for significance. In addition to ongoing analysis of conditioning-mediated cytokine induction and clinical response, we are evaluating the impact of conditioning chemotherapy dose on cytokine levels, as well as the relationship between conditioning-related cytokines and CAR T-cell expansion and persistence.Conclusions: The data obtained to date support the hypothesis that cytokines such as IL-15 play a key role in the clinical outcomes to anti-CD19 CAR T-cell therapy. Our results demonstrate that conditioning chemotherapy significantly increases the levels of homeostatic cytokines known to regulate T-cell expansion, as well as specific pro-inflammatory cytokines and chemokines. Optimization of conditioning chemotherapy is critical to the activity of CAR T-cell therapies. DisclosuresBot:Kite Pharma: Employment, Equity Ownership. Rossi:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Navale:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Shen:Kite Pharma: Employment, Equity Ownership. Sherman:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Mardiros:Kite Pharma: Employment, Equity Ownership. Yoder:Kite Pharma: Employment, Equity Ownership. Go:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Rosenberg:Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Chang:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Roberts:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma.

Cytokines as Suicide Risk Biomarkers

Suicide is a major public health problem as about 40,000 people die by suicide in the United States annually. Prevention and treatment of suicidal behavior are therefore very important. The major problem in the prevention of suicide is early identification and treatment of suicide-prone patients. Suicide is a multifactorial problem involving clinical, genetic, and neurobiological risk factors. The identification of risk factors that could accurately predict completed suicide has been investigated by many researchers. Meta-Analysis of Cytokines and Chemokines in Suicidality: Distinguishing Suicidal Versus Nonsuicidal PatientsBiological PsychiatryVol. 78Issue 1PreviewMajor psychiatric disorders are associated with inflammation. Aberrant cytokine and chemokine levels have been associated with psychiatric disorders and suicidal behavior. We performed a meta-analysis of cytokine and chemokine levels in patients with versus without suicidality and patients with suicidality versus healthy controls. Full-Text PDF

Dynamics Changes in CCL3 and CCL4 Plasma Chemokine Levels in Patients with Chronic Lymhocytic Leukemia (CLL) Managed with Observation

Background: CCL3 and CCL4, previously called macrophage inflammatory protein-1 alpha (MIP-1α) and MIP-1β, are chemokines of the CC subfamily, which are secreted by CLL cells in response to B cell receptor (BCR) stimulation and by co-culture with nurse-like cells (NLC), presumably to attract T lymphocytes and monocytes that can deliver pro-survival signals. We previously reported, that CLL patients have elevated plasma levels of CCL3 and CCL4, which rapidly normalize after treatment with kinase inhibitors that target BCR signaling, such as the BTK inhibitor ibrutinib and the PI3K inhibitor idelalisib (Blood 119:1182-9, 2012)(Blood 118:3603-12, 2011). Moreover, in untreated CLL patients, high CCL3 levels are an independent prognostic marker for short time to disease progression (Blood 117:1662-9, 2011), emphasizing the clinical relevance of these chemokines in CLL.Aim: To better understand the dynamic changes, we analyzed plasma levels of CCL3 and CCL4 in a large cohort of serial samples from untreated CLL patients. Additionally, we analyzed separately from the entire cohort, CCL3 and CCL4 changes overtime in patients who subsequently received therapy and patients who were still on observation at time of analysis.Methods: CCL3 and CCL4 plasma levels were measured by ELISA in serial samples collected over time in untreated CLL patients. A total of 193 individual patients with 603 plasma samples were included in the analysis (entire cohort), of the 193 patients, 81 of them required treatment at a later time, although all the samples analyzed were collected prior any treatment, 112 patients did not need any intervention over the period of sample collection and were managed with observation. The duration between first and subsequent samples ranged between 5 months to 12 years. The duration between the date of the last sample and the date of the initiation of treatment ranged between less than a month to 88 months with a median of 6 months. Mixed linear models with repeated measure were used to determine whether there was a difference in mean levels of CCL3 and CCL4 over time.Results: The median and range of CCL3 and CCL4 levels for the initial sample over all 193 patients were 11.8 pg/mL (2.5 – 1977.1 pg/mL) and 88.8 pg/mL (6.9 – 2601.3 pg/mL) respectively. There were significant associations of time between first and subsequent serial samples (p<0.0001) and log of baseline CCL3 (p<0.0001) with log of CCL3 measurements over time, in both the watchful waiting and treated patient’s cohort; same associations were found for CCL4. Overall, we found that there was an increase by a factor of 1.009/month in CCL3 and 1.006/month for CCL4 in the group of patients managed with observation, and 1.01/month in CCL3 and 1.011/month in CCL4 in the group of patients that were eventually treated.Conclusions: These studies demonstrated that there is a slight but statistically significant increase in the levels of the chemokines CCL3 and CCL4 over time in CLL patients, regardless of whether the patients required therapy at a later time. We conclude that CCL3 and CCL4 plasma levels presumably reflect the dynamic changes of CLL pathogenesis over time, strengthening the relevance of CCL3 and CCL4 chemokine production in CLL. DisclosuresNo relevant conflicts of interest to declare.

Increased serum levels of interleukin-8 in patients with tension-type headache.

The pathophysiology of tension-type headache is not well understood. Increased peripheral levels of pro-inflammatory cytokines may act as mediators of several chronic pain disorders. The aim of the present study was to investigate the peripheral levels of chemokines in patients with tension-type headache. This was a cross sectional study evaluating serum levels of chemokines in age and sex-matched tension-type headache patients, ictally and interictally, and control participants. Beck Depression and Anxiety Inventories were recorded. Serum levels of monocyte chemoattractant protein-1, macrophage inflammatory protein 1α, regulated on activation, normal T cell expressed and secreted, eotaxin, eotaxin-2, interleukin-8, interferon gamma induced protein-10 were measured by enzyme-linked immunosorbent assay. A total of 96 participants (48 tension-type headache, 48 controls) were included. Interleukin-8 levels were significantly increased in patients with tension-type headache when compared to controls (413.8 (123.4-1756.3) and 329 (107.8-955.6), respectively, P = 0.025). Anxiety and depression scores were higher in patients with tension-type headache but interleukin-8 increase in tension-type headache patients persisted after controlling for anxiety and depression symptoms. Patients with headache at the time of assessment had increased monocyte chemoattractant protein-1 levels when compared with patients without headache (2809.3 (1101-6122.2) and 1630.2 (669.3-31056.8), respectively P = 0.026). Patients with episodic and chronic tension-type headache had no significant differences in serum chemokines levels. Interleukin-8 was increased in tension-type headache and monocyte chemoattractant protein-1 was higher in tension-type headache patients with headache, suggesting that pro-inflammatory mechanisms may participate in tension-type headache pathophysiology.

Meta-Analysis of Cytokines and Chemokines in Suicidality: Distinguishing Suicidal Versus Nonsuicidal Patients

BackgroundMajor psychiatric disorders are associated with inflammation. Aberrant cytokine and chemokine levels have been associated with psychiatric disorders and suicidal behavior. We performed a meta-analysis of cytokine and chemokine levels in patients with versus without suicidality and patients with suicidality versus healthy controls. MethodsWe identified articles by searching MEDLINE, PsycINFO, and Thomson Reuters Web of Knowledge databases and the reference lists of identified studies. ResultsStudy inclusion criteria were met by 18 studies comprising 583 patients with suicidality, 315 patients without suicidality, and 845 healthy control subjects. Levels of interleukin (IL)-1β and IL-6 were significantly increased in blood and postmortem brain samples of patients with suicidality compared with both patients without suicidality and healthy control subjects (p < .05 for each). In vitro IL-2 production by peripheral blood mononuclear cells was significantly decreased in patients with suicidality compared with both patients without suicidality and healthy controls (p < .01 for each). Cerebrospinal fluid levels of IL-8 were significantly decreased in patients with suicidality versus control subjects (p < .05). ConclusionsWe found evidence for aberrant cytokine levels in blood, cerebrospinal fluid, and postmortem brain samples of patients with suicidality. Levels of IL-1β and IL-6 were most robustly associated with suicidality, and these cytokines may help distinguish suicidal from nonsuicidal patients. Rigorously designed longitudinal studies are needed to evaluate these associations further.

Significantly Higher Cytokine and Chemokine Levels in Patients with Japanese Spotted Fever than in Those with Tsutsugamushi Disease

Tetracyclines are administered to cure Japanese spotted fever (JSF) and tsutsugamushi disease (TD). It is generally said that the clinical course of JSF is worse than that of TD despite antibiotic treatment. The precise mechanism underlying the more severe clinical course of JSF is not fully understood. We therefore examined whether the differential cytokine profile between these two infectious diseases contributes to the difference in clinical severity. The serum concentrations of various cytokines (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6], and gamma interferon [IFN-γ]) and chemokines (IL-8, interferon-inducible protein 10 [IP-10], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1α [MIP-1α], MIP-1β, and eotaxin) were measured in 32 TD and 21 JSF patients. The results showed that serum levels of TNF-α in the acute phases of TD and JSF were significantly increased, with a higher concentration of TNF-α in patients with JSF (mean, 39.9 pg/ml) than in those with TD (mean, 13.8 pg/ml). Comparatively higher levels of other cytokines and chemokines (IL-6, IFN-γ, IL-8, IP-10, MCP-1, MIP-1α, and MIP-1β) were also observed in the acute phase of JSF. The clinical severity score (3.67 ± 1.71) of JSF patients was higher than that of TD patients (1.47 ± 0.77). Our findings revealed that the cytokine and chemokine levels in the acute phase of JSF were significantly higher than those in the acute phase of TD. The differential cytokine levels may be related to the difference in clinical severity between JSF and TD.

Alterations in cytokines and haematological parameters during the acute and convalescent phases of Plasmodium falciparum and Plasmodium vivax infections.

Haematological and cytokine alterations in malaria are a broad and controversial subject in the literature. However, few studies have simultaneously evaluated various cytokines in a single patient group during the acute and convalescent phases of infection. The aim of this study was to sequentially characterise alterations in haematological patters and circulating plasma cytokine and chemokine levels in patients infected with Plasmodium vivax or Plasmodium falciparum from a Brazilian endemic area during the acute and convalescent phases of infection. During the acute phase, thrombocytopaenia, eosinopaenia, lymphopaenia and an increased number of band cells were observed in the majority of the patients. During the convalescent phase, the haematologic parameters returned to normal. During the acute phase, P. vivax and P. falciparum patients had significantly higher interleukin (IL)-6, IL-8, IL-17, interferon-γ, tumour necrosis factor (TNF)-α, macrophage inflammatory protein-1β and granulocyte-colony stimulating factor levels than controls and maintained high levels during the convalescent phase. IL-10 was detected at high concentrations during the acute phase, but returned to normal levels during the convalescent phase. Plasma IL-10 concentration was positively correlated with parasitaemia in P. vivax and P. falciparum-infected patients. The same was true for the TNF-α concentration in P. falciparum-infected patients. Finally, the haematological and cytokine profiles were similar between uncomplicated P. falciparum and P. vivax infections.

Low level of inflammatory marker in hyperhomocysteinemic patients on statin therapy

Inflammatory processes including increased activation of chemokines play an important role in atherogenesis. Patients with hyperhomocysteinemia have increased risk for cardiovascular events that potentially involve enhanced inflammation. Statins may have anti-inflammatory actions at least partly independent on their lipid-lowering effects. In the present study we examined the association between statins and chemokine levels in patients with hyperhomocysteinemia. Our major findings were (i) patients with hyperhomocysteinemia on statin treatment (n = 14) have significantly lower plasma levels of the CXC chemokine epithelial neutrophil activating peptide (ENA)-78 compared to hyperhomocysteinemic patients not on statin treatment (n = 8). In fact, levels of ENA-78 in statin-treated patients did not differ from those of healthy controls (n = 17); (ii) plasma levels of ENA-78 and growth-related oncogene (GRO)α correlated with levels of LDL-cholesterol and homocysteine; (iii) in contrast, plasma levels of the CC chemokine monocyte chemoattractant peptide (MCP)-1 were similar between statin-users, non-statin users and controls, and did not correlate with levels of LDL-cholesterol or homocysteine; and (iv) in vitro studies showed that simvastatin significantly reduced release of ENA-78, GROα and MCP-1 from peripheral blood mononuclear cells in healthy controls (n = 7) in a concentration-dependent manner, without affecting release of RANTES. Our data may suggest that ENA-78 and GROα may be involved in the inflammatory arm of atherogenesis in patients with elevated risk of cardiovascular disease, with potential down-regulatory effect of statins.

CCL19, a B Cell Chemokine, Is Related to the Decrease of Blood Memory B Cells and Predicts the Clinical Response to Rituximab in Patients With Rheumatoid Arthritis

Migration of B cells from peripheral blood to the synovium in patients with rheumatoid arthritis (RA) may predict clinical response to rituximab (RTX). We undertook this study to investigate whether serum levels of chemokines involved in B cell trafficking are correlated with blood levels of memory B cells or serum levels of B cell activation biomarkers before B cell depletion and whether chemokine levels predict RTX responsiveness. Blood B cell subsets were analyzed by flow cytometry (CD27, IgD), and serum B cell activation biomarkers (rheumatoid factor, anti-cyclic citrullinated peptide, free light chains, IgG, IgA, IgM, and BAFF) were measured in 208 RA patients and 70 control subjects. Serum CCL19, CXCL12, and CXCL13 chemokine levels in patients and controls were determined by enzyme-linked immunosorbent assay. The first course of RTX was administered to RA patients, and the response was evaluated at week 24 according to European League Against Rheumatism (EULAR) criteria. Results were expressed as the odds ratio (OR) and 95% confidence interval (95% CI). Levels of all chemokines were increased in RA patients compared with controls, and levels were inversely correlated with CD27+ memory B cell frequency. CCL19 and CXCL13 levels correlated with levels of 6 serum B cell biomarkers and 4 serum B cell biomarkers, respectively. By univariate analysis, the CCL19 level was positively associated with EULAR response (OR 1.43 [95% CI 1.08-1.90], P = 0.01). By multivariate analysis, the CCL19 level was predictive of a response to RTX (OR 1.48 [95% CI 1.06-2.06], P = 0.02), but this did not persist after adjustment for autoantibody status. CXCL13 and CCL19 reflect blood B cell disturbances and their levels correlate with those of other serum B cell biomarkers. CXCL13 and CCL19 are, therefore, surrogate measures for serum B cell biomarkers in RA. Serum CCL19 measurement is a new hallmark of the B cell-mediated RA subtype and may predict clinical response to RTX.

Diagnostic Value of Cytokines and Chemokines in Lyme Neuroborreliosis

The aims of the present study were to assess the concentrations of different cytokines and chemokines in blood serum and cerebrospinal fluid (CSF) samples of patients with Lyme neuroborreliosis and to identify the possible marker(s) that would enable a distinction between clinically evident and suspected Lyme neuroborreliosis, as well as between Lyme neuroborreliosis and tick-borne encephalitis (TBE). Our additional interest was to evaluate the relationship between cytokine and chemokine concentrations and Borrelia burgdorferi sensu lato isolation from CSF, as well as intrathecal synthesis of specific borrelial antibodies. We found that higher concentrations of CXCL13 and lower concentrations of interleukin 10 (IL-10) in serum were associated with higher odds for clinically evident Lyme neuroborreliosis compared to suspected Lyme neuroborreliosis, as well as to TBE. The concentrations of IL-2, IL-5, IL-6, IL-10, and CXCL13 in the CSF were higher in patients with evident Lyme neuroborreliosis than in those who were only suspected to have the disease. A comparison of CSF cytokine and chemokine levels in patients with and without intrathecal synthesis of specific borrelial antibodies revealed that CXCL13 CSF concentration is significantly associated with intrathecal synthesis of borrelial antibodies. A comparison of the cytokine and chemokine CSF concentrations in patients with clinically evident Lyme neuroborreliosis according to CSF culture results revealed that higher concentrations of gamma interferon (IFN-γ) were associated with lower odds of Borrelia isolation. Although several differences in the blood serum and CSF concentrations of various cytokines and chemokines between the groups were found, the distinctive power of the majority of these findings is low. Further research on well-defined groups of patients is needed to appraise the potential diagnostic usefulness of these concentrations.

Reduction of CC-chemokine ligand 5 by aryl hydrocarbon receptor ligands

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that recognizes a large number of xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs), dioxins, and some endogenous ligands. Despite numerous investigations targeting AhR ligands, the precise physiological role of AhR remains unknown. We explored novel AhR target genes, especially focused on inflammatory chemokine. We treated (1) HaCaT, a human keratinocyte cell line, (2) normal human epidermal keratinocytes (NHEKs), and (3) mouse primary keratinocytes with AhR ligands, such as 6-formylindolo[3,2-b]carbazole (FICZ; endogenous ligand) and benzo[a]pyrene (BaP; exogenous ligand). Then, we detected mRNA and protein of chemokine using quantitative RT-PCR and ELISA. We next clarified the relationship between AhR and chemokine expression using AhR siRNA. In addition, we measured serum chemokine levels in patients with Yusho disease (oil disease), who were accidentally exposed to dioxins in the past. We identified CC-chemokine ligand 5 (CCL5), a key mediator in the development of inflammatory responses, as the AhR target gene. AhR ligands (FICZ and BaP) significantly reduced CCL5 mRNA and protein expression in HaCaT cells. These effects were observed in NHEKs and mouse primary keratinocytes. AhR knockdown with siRNA restored CCL5 inhibition by AhR ligands. In addition, AhR ligands exhibited a dose-dependent suppression of CCL5 production induced by Th1-derived cytokines. Finally, serum levels of CCL5 in patients with Yusho disease, were significantly lower than in controls. Our findings indicate that CCL5 is a target gene for AhR, and might be associated with the pathology of dioxin exposure.