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Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) remains an ongoing clinical challenge. We investigated plasma biomarkers and their association with 6-month outcomes in a nonhuman primate model of HIE with or without therapeutic hypothermia (TH) and erythropoietin (Epo). Twenty-nine Macaca nemestrina were randomized to control cesarean section (n = 7) or 20 min of umbilical cord occlusion (UCO, n = 22) with either no treatment (n = 11) or TH/Epo (n = 11). Initial injury severity was scored using 30-min arterial pH, base deficit, and 10-min Apgar score. Twenty-four plasma cytokines, chemokines, and growth factors were measured 3, 6, 24, 72, and 96 h after UCO. Interleukin 17 (IL-17) and macrophage-derived chemokine (MDC) differentiated the normal/mild from moderate/severe injury groups. Treatment with TH/Epo was associated with increased monocyte chemotactic protein-4 (MCP-4) at 3 h-6h, and significantly lower MCP-4 and MDC at 24 h-72h, respectively. IL-12p40 was lower at 24 h-72h in animals with death/cerebral palsy (CP) compared to survivors without CP. Baseline injury severity was the single best predictor of death/CP, and predictions did not improve with the addition of biomarker data. Circulating chemokines associated with the peripheral monocyte cell lineage are associated with severity of injury and response to therapy, but do not improve ability to predict outcomes.

Identification of novel immune biomarkers to gauge the underlying pathology and severity of COVID-19 has been difficult due to the lack of longitudinal studies. Here, we analyzed serum collected upon COVID-19 admission (t1), 48 hours (t2), and seven days later (t3) using Olink proteomics and correlated to clinical, demographics, and therapeutic data. Older age positively correlated with decorin, pleiotrophin, and TNFRS21 but inversely correlated with chemokine (both C-C and C-X-C type) ligands, monocyte attractant proteins (MCP) and TNFRS14. The burden of pre-existing conditions was positively correlated with MCP-4, CAIX, TWEAK, TNFRS12A, and PD-L2 levels. Individuals with COVID-19 demonstrated increased expression of several chemokines, most notably from the C-C and C-X-C family, as well as MCP-1 and MCP-3 early in the course of the disease. Similarly, deceased individuals had elevated MCP-1 and MCP-3 as well as Gal-9 serum levels. LAMP3, GZMB, and LAG3 at admission correlated with mortality. Only CX3CL13 and MCP-4 correlated positively with APACHE score and length of stay, while decorin, MUC-16 and TNFRSF21 with being admitted to the ICU. We also identified several organ-failure-specific immunological markers, including those for respiratory (IL-18, IL-15, Gal-9) or kidney failure (CD28, VEGF). Treatment with hydroxychloroquine, remdesivir, convalescent plasma, and steroids had a very limited effect on the serum variation of biomarkers. Our study identified several potential targets related to COVID-19 heterogeneity (MCP-1, MCP-3, MCP-4, TNFR superfamily members, and programmed death-ligand), suggesting a potential role of these molecules in the pathology of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Laudanski, Jihane, Antalosky, Ghani, Phan, Hernandez, Okeke, Wu, Rader and Susztak.)

Stanford type A Aortic dissection (TAAD) is a deadly cardiovascular disease but the relationship between inflammatory cytokines and disease pathogenesis is still unclear. Observation of the changes of different chemokines may help to explore the etiology of TAAD much further. Clinical data was collected from TAAD patients (TAAD group) and healthy controls (HC group) in our institute between October 2013 and December 2014. Blood sample was harvested from each subject of two groups. The expression levels of eighty chemokines were examined by protein array technology. Then we tested the expressions of macrophage inflammatory protein 1β (MIP-1β), epithelial neutrophil activating peptide 78 (ENA-78), interleukin 16 (IL-16), interferon inducible protein 10 (IP-10), and FMS-like tyrosine kinase 3 (Flt-3) ligand by using luminex technology. Osteopontin (OPN) and monocyte chemotaxis protein (MCP) levels were analyzed by ELISA kits. The mean age of TAAD group is 49.9 ± 11.2 and 48.7 ± 9.9 in HC group, respectively. 76.0% of TAAD patients and 72.0% of healthy controls were male. MIP-1β and ENA-78 expression in TAAD group were significantly lower than that in HC group, while significant increasing IL-16 level was found. Plasma levels of OPN in TAAD group increased remarkably compared with HC group, but MCP-1 and MCP-2 expression significantly decreased. No correlation was shown between serum CRP levels and plasma level of these cytokines by using Spearman analysis. ROC analysis showed that OPN could be indicators for TAAD diagnosis with sensitivity of 0.92 and specificity of 0.99. Our results provide a reasonable way to focus on the chemokines in understanding the pathogenesis of human TAAD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Inflammation is considered a hallmark of concussion pathophysiology in experimental models, yet is understudied in human injury. Despite the growing use of blood biomarkers in concussion, inflammatory biomarkers have not been well characterized. Furthermore, it is unclear if the systemic inflammatory response to concussion differs from that of musculoskeletal injury. The purpose of this paper was to characterize systemic inflammation after injury in athletes with sport-related concussion or musculoskeletal injury., Methods: A prospective, observational cohort study was conducted employing 175 interuniversity athletes (sport-related concussion, n = 43; musculoskeletal injury, n = 30; healthy, n = 102) from 12 sports at a sports medicine clinic at an academic institution. High-sensitivity immunoassay was used to evaluate 20 inflammatory biomarkers in the peripheral blood of athletes within 7 days of injury (subacute) and at medical clearance. Healthy athletes were sampled prior to the start of their competitive season. Partial least squares regression analyses were used to identify salient biomarker contributions to class separation between injured and healthy athletes, as well as to evaluate the relationship between biomarkers and days to recovery in injured athletes., Results: In the subacute period after injury, compared to healthy athletes, athletes with sport-related concussion had higher levels of the chemokines' monocyte chemoattractant protein-4 (p < 0.001) and macrophage inflammatory protein-1β (p = 0.001); athletes with musculoskeletal injury had higher levels of thymus and activation-regulated chemokine (p = 0.001). No significant differences in biomarker profiles were observed at medical clearance. Furthermore, concentrations of monocyte chemoattractant protein-1 (p = 0.007) and monocyte chemoattractant protein-4 (p < 0.001) at the subacute time point were positively correlated with days to recovery in athletes with sport-related concussion, while thymus and activation-regulated chemokine was (p = 0.001) positively correlated with days to recovery in athletes with musculoskeletal injury., Conclusion: Sport-related concussion is associated with perturbations to systemic inflammatory chemokines that differ from those observed in athletes with a musculoskeletal injury. These results support inflammation as an important facet of secondary injury after sport-related concussion that can be measured systemically in a human model of injury.

Objectives: The aim of this study was to investigate the association between dairy product consumption and plasma inflammatory biomarkers levels among a representative sample of Brazilian adults from São Paulo City., Methods: Data were acquired from the Health Survey for São Paulo, a cross-sectional population-based study. All individuals 20 to 59 y of age with complete food consumption information (24-h dietary recall and food frequency questionnaire) and blood sample analysis were included (N = 259). The sample was separated into two groups according to systemic inflammatory pattern considering plasma levels of C-reactive protein; tumor necrosis factor-α; soluble intracellular adhesion molecule; soluble vascular cell adhesion molecule, monocyte chemoattractant protein; interleukin-1β, -6, -8, -10, and -12; adiponectin; leptin; and homocysteine. Multiple logistic regression tests were conducted to estimate the odds ratio for the inflammatory cluster across tertiles of dairy consumption., Results: When adjusted by age, smoking status, and energy intake the odds ratio for the inflammatory cluster group in the highest tertile of yogurt consumption was 0.34 (95% confidence interval [CI], 0.14-0.81) relative to the reference tertile, demonstrating also a linear effect (P trend  = 0.015). Cheese consumption exhibited an odds ratio of 2.49 (95% CI, 1.09-5.75) relative to the reference., Conclusions: Increasing yogurt consumption might have a protective effect on inflammation, whereas cheese consumption appears to be associated with a proinflammatory status. The results of the present study aggregate a new perspective on existing evidence demonstrating the importance of assessing the contribution of dairy products on diet and their effect on the development of non-communicable diseases and associated risk factors., (Copyright © 2017. Published by Elsevier Inc.)

Major overlaps of clinical characteristics and the limitations of conventional diagnostic tests render the initial diagnosis and clinical management of pulmonary disorders difficult. In this pilot study, we analyzed the predictive value of eotaxin, macrophage inflammatory protein 1 alpha (MIP-1α), monocyte chemoattractant protein 4 (MCP-4), and vascular endothelial growth factor (VEGF) in 40 patients hospitalized with acute lower respiratory tract infections (LRTI). The cytokines contribute to the pathogenesis of several inflammatory respiratory diseases, indicating a potential as markers for LRTI. Patients were stratified according to etiology and severity of LRTI, based on baseline C-reactive protein and CURB-65 scores. Using a multiplex immunoassay of plasma, levels of eotaxin and MCP-4 were shown to increase from baseline until day 6 after admission to hospital. The four cytokines were unable to predict the etiology and severity. Eotaxin and MCP-4 were significantly lower in patients with C-reactive protein ≥100, and MIP-1α was significantly higher in the patients with CURB-65 > 3, but the predictive power was low. In conclusion, further evaluation, including more patients, is required to assess the full potential of eotaxin, MCP-4, MIP-1α, and VEGF as biomarkers for LRTI because of their low predictive power and a high interindividual variation of cytokine levels., (© 2016 APMIS. Published by John Wiley & Sons Ltd.)

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

Purpose: Despite recent progress in the diagnosis and treatment of colorectal cancer (CRC), the prognosis remains poor, and metastatic recurrence is the leading cause of poor prognosis. We systemically evaluated the levels of differentially-expressed serum cytokines using array-based techniques to identify a novel and reliable serum biomarker with which to predict metastasis and poor outcomes of CRC., Methods: We examined cytokine profiling using preoperative serum from two different cohorts to identify differentially-expressed serum cytokines in patients with metastatic CRC. In the validation phase, serum monocyte chemotactic protein-4 (MCP-4) concentration was assessed in 194 patients by enzyme-linked immunosorbent assay, and its relationships with clinicopathological findings were investigated., Results: In discovery phase, three cytokines were differentially expressed in serum from patients with metastatic CRC. In validation phase, high MCP-4 was significantly associated with older age, advanced T stage, distant metastasis, and UICC stage. Cox regression analysis showed that elevated MCP-4 was an independent prognostic factor of disease-free survival and overall survival. Furthermore, logistic regression analysis revealed that high serum MCP-4 was an independent predictor of distant metastasis., Conclusion: Quantification of serum MCP-4 concentration might support the early detection/prediction of recurrence and may contribute to the prediction of clinical outcomes in CRC. J. Surg. Oncol. 2016;114:483-489. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The long-term health effects of concussion and sub-concussive impacts in sport are unknown. Growing evidence suggests both inflammation and neurodegeneration are pivotal to secondary injury processes and the etiology of neurodegenerative diseases. In the present study we characterized circulating brain injury and inflammatory mediators in healthy male and female athletes according to concussion history and collision sport participation. Eighty-seven university level athletes (male, n = 60; female, n = 27) were recruited before the start of the competitive season. Athletes were healthy at the time of the study (no medications, illness, concussion or musculoskeletal injuries). Dependent variables included 29 inflammatory and 10 neurological injury analytes assessed in the peripheral blood by immunoassay. Biomarkers were statistically evaluated using partial least squares multivariate analysis to identify possible relationships to self-reported previous concussion history, number of previous concussions and collision sport participation in male and female athletes. Multiple concussions were associated with increases in peripheral MCP-1 in females, and MCP-4 in males. Collision sport participation was associated with increases in tau levels in males. These results are consistent with previous experimental and clinical findings that suggest ongoing inflammatory and cerebral injury processes after repetitive mild head trauma. However, further validation is needed to correlate systemic biomarkers to repetitive brain impacts, as opposed to the extracranial effects common to an athletic population such as exercise and muscle damage.

Objective: CCL13, a recently identified CC chemokine, plays an important role in the process of joint destruction, which is considered a common cause for osteoarthritis (OA). This study aims to examine the relation of CCL13 levels in serum and synovial fluid (SF) with the radiographic severity of OA., Methods: CCL13 levels in serum and SF were evaluated using enzyme-linked immunosorbent assay method in 240 patients with knee OA and 134 control subjects. The progression of OA was classified using the Kellgren-Lawrence (KL) system by evaluating x-ray changes observed in anteroposterior knee radiography., Results: Knee OA patients had higher levels of serum CCL13 compared with control subjects. Knee OA patients with KL grade 4 showed significantly elevated CCL13 levels in serum and SF compared with those with KL grades 2 and 3. Knee OA patients with KL grade 3 had significantly higher SF levels of CCL13 compared with those with KL grade 2. CCL13 levels in serum and SF of knee OA patients were significantly correlated with disease severity evaluated by KL grading criteria., Conclusions: CCL13 levels in serum and SF were correlated with the radiographic severity of OA. CCL13 levels in serum and SF may serve as a biomarker for the progression of OA.

We evaluated commercially available bovine enzyme linked immunosorbent assays (ELISA) and a human IP-10 ELISA to measure IP-10, MIG, MCP-1, MCP-2, MCP-3 and IL1-RA in buffalo plasma in order to identify sensitive markers of the immune response to Mycobacterium bovis-specific peptides. Additionally, we found that all coding mRNA sequences of these cytokines showed very high homology with their homologues in domestic cattle (97-99%) as did the derived amino acid sequences (97-99%). This high sequence homology between cattle and buffaloes supports the use of bovine ELISAs for the detection these cytokines in buffaloes. MCP-1 concentration showed a positive correlation with that of IFN-γ (p=0.0077) and appears to occur in far greater abundance in buffaloes when compared to humans. Using a bovine IP-10 ELISA, levels of this cytokine were found to be significantly increased in antigen-stimulated blood samples from M. bovis test positive buffaloes (p<0.0001) and IP-10 was detected in far greater abundance than IFN-γ. Measurement of IP-10 with this ELISA may prove to be a sensitive marker of M. bovis infection in African buffaloes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Although rectal bleeding in infancy (RBI) is not a rare phenomenon, the clinical course of RBI is not fully understood., Methods: To investigate the outcome and pathogenesis of RBI, especially when concomitant with food-protein-induced proctocolitis (FPIP) and neonatal transient eosinophilic colitis (NTEC), 22 neonates with rectal bleeding with FPIP and NTEC from January 2008 to June 2012 were enrolled and their clinical course and mechanisms of inflammation were examined., Results: Thirteen infants showed rectal bleeding after feeding and were diagnosed with FPIP, and nine infants showed rectal bleeding before feeding and were diagnosed with NTEC. Elevated peripheral white blood cell (12,685 ± 3754/μl and 30,978 ± 16,166/μl) and eosinophil (1084 ± 816/μl and 4456 ± 3341/μl) were confirmed in FPIP and NTEC, respectively. Colonoscopy revealed nodular lymphoid hyperplasia, a pale mucosal surface and oozing with diffuse infiltration of neutrophils, lymphocytes, and eosinophils in both groups. Reverse transcription polymerase chain reaction analysis revealed enhanced expression of the interleukin-6, CCL11, and CXCL13 genes, where CXCL13 expression was more prominent in FPIP. Mucosal infiltration by CD3- and immunoglobulin-A- but not immunoglobulin-E-positive cells was confirmed. Among them, only one infant with FPIP developed milk allergy, whereas none with NTEC had developed milk allergy at the age of 1 year., Conclusions: FPIP in infancy and NTEC are similar diseases and interleukin-6, CCL11, and CXCL13 may play a major role in the pathogenesis of rectal bleeding. Although the involvement of allergic reaction is possible, milk allergy was not a common outcome after 1 year of follow up., (© 2014 Japan Pediatric Society.)

Background: Asthma is a disease with marked heterogeneity in its clinical course and response to treatment. IL-13 is central to type 2 inflammation, which contributes to many key features of asthma. Lebrikizumab is an anti-IL-13 mAb previously reported to significantly improve lung function in patients with inadequately controlled asthma despite inhaled corticosteroid therapy, especially in periostin-high patients., Objective: This phase II study investigated the efficacy and safety of IL-13 blockade with different doses of lebrikizumab in asthmatic patients not receiving inhaled corticosteroids., Methods: Patients were randomized to receive 125, 250, or 500 mg of lebrikizumab or placebo subcutaneously monthly for 12 weeks with an 8-week follow-up period. The primary efficacy end point was the relative change in prebronchodilator FEV1 from baseline to week 12., Results: A total of 212 patients were randomized. The mean relative change in FEV1 was numerically higher in all lebrikizumab dose groups versus the placebo group, although the difference was neither statistically nor clinically significant. There were no meaningful differences in changes in FEV1 between the dose groups and the placebo group by the periostin subgroup. Lebrikizumab treatment was associated with a reduced risk of treatment failure at all doses versus placebo (P < .001), and results were similar by the periostin subgroup, with no apparent differences between doses of lebrikizumab. Lebrikizumab was generally well tolerated., Conclusion: Blocking IL-13, a single cytokine, in this population of asthmatic patients is insufficient to improve lung function. There is evidence that IL-13 blockade may improve disease control, as measured by prevention of protocol-defined treatment failure in these patients., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Objectives: CC motif chemokines are considered to be implicated in the pathogenesis of rheumatoid arthritis (RA) via recruitment of monocytes and lymphocytes. CC motif chemokine ligand 13 (CCL13)/monocyte chemoattractant protein-4 (MCP-4) is postulated to be a potent RA inducer. We conducted a study to more precisely clarify the role of CCL13 in RA pathogenesis., Methods: CCL13 expression was evaluated by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining in serum samples and synovial tissues from RA patients. The effects of CCL13 against apoptosis were monitored on cultured synovial fibroblasts. The chemoattractant activity of CCL13 was evaluated by the Boyden chamber assay in monocytes (THP-1 cells) and human umbilical vein endothelial cells (HUVECs)., Results: We found that CCL13 serum level and synovial tissue expression were increased in RA patients. CCL13 had chemoattractant activity for both THP-1 cells and HUVECs. Interestingly, CCL13 expression was positively regulated by tumor necrosis factor-alpha (TNF-α). Furthermore, apoptosis induced by hydrogen peroxide (H2O2) and serum deprivation was inhibited by CCL13 on the cultured synovial fibroblasts., Conclusions: CCL13 may be associated with disease progression as a result of its antiapoptotic effects, increased macrophage infiltration, and synovial tissue angiogenesis in RA patients.

Chemokines and cytokines play a vital role in directing and regulating immune responses to viral infections. Persistent hepatitis C virus (HCV) infection is characterized by the loss of anti-HCV cellular immune responses, while control of HCV infection is associated with maintenance of anti-HCV cellular immune responses. To determine whether plasma concentrations of 19 chemokines and cytokines controlling T-cell trafficking and function differed based on infection outcome, we compared them in at-risk subjects followed prospectively for HCV infection. Levels were compared over time in subjects who controlled HCV infection (Clearance) and subjects who developed persistent HCV infection (Persistence) at two time points during acute infection: (i) first viraemic sample (initial viraemia) and (ii) last viraemic sample in Clearance subjects and time-matched samples in Persistence subjects. At initial viraemia, increased pro-inflammatory tumour necrosis factor α (TNFα) plasma concentrations were observed in the Clearance group, while the plasma levels of anti-inflammatory interleukin (IL)-2, IL-10 and IL-13 were higher in the Persistence group. IL-13 was positively correlated with IL-2 and IL-10 at initial viraemia in the Persistence group. At the time of last viraemia, plasma levels of eotaxin, macrophage chemoattractant protein-4 (MCP-4), IL-5 and IL-10 were higher in the Persistence group and IL-10 and IL-5 levels were positively correlated. Collectively, these results suggest that the development of persistent infection is associated with an anti-inflammatory and pro-fibrogenic chemokine and cytokine profile that is evident at the onset of infection and maintained throughout acute infection., (© 2013 John Wiley & Sons Ltd.)

Objectives: Obesity is increasing in prevalence worldwide and has emerged as a strong risk factor for periodontal disease. Conversely, the remote effects of periodontal disease on various systemic diseases have been proposed. The aim of this study is to determine the presence of MCP-4 and high sensitivity C reactive protein (hsCRP) levels in gingival crevicular fluid (GCF) and serum in obese and non-obese subjects with chronic periodontitis and to find a correlation between MCP-4 and hsCRP in GCF and serum., Materials and Methods: Forty subjects (20 males and 20 females) were selected and divided into four groups (10 subjects in each group), based on clinical parameters: group NOH (non-obese healthy), group OH (obese healthy), Group NOCP (non-obese with chronic periodontitis) and group OCP (obese with chronic periodontitis). The levels of serum and GCF MCP-4 were determined by ELISA and hsCRP levels were determined by immunoturbidimetry method., Results: The mean GCF and serum concentration of MCP-4 was highest for group OCP followed by group NOCP, group OH (in GCF); group OH, group NOCP(in serum) and least in group NOH. The mean hsCRP concentration was highest for group OCP followed by group OH, group NOCP and group NOH. A significant positive correlation was found between serum and GCF MCP-4 and hsCRP levels., Conclusion: GCF MCP-4 concentrations increased in periodontal disease compared to health and correlated positively with the severity of disease indicating it as a novel marker of periodontal disease. The serum concentration of MCP-4 was found to be more in obese group as compared to nonobese group indicating it as a marker of obesity. Furthermore, based on the positive correlation of MCP-4 and hsCRP found in this study, it can be proposed that MCP-4 and hsCRP may be the markers linking chronic inflammation in obesity and periodontal disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Transfusion of packed red blood cells (PRBCs) saves lives in the neonatal critical care setting and is one of the most common interventions in the preterm infant. The number and volume of PRBC transfusions are associated with several major neonatal morbidities, although a direct causal link between transfusion and major neonatal morbidity is still to be proven. Transfusion-related immunomodulation (TRIM) may underlie these adverse outcomes, yet it has received little attention in the high-risk preterm infant., Methods: One transfusion event was studied in infants ≤28 wk gestation between 2 and 6 wk postnatal age (n = 28). Plasma inflammatory cytokines and markers of endothelial activation were measured in the infants before and 2-4 h after transfusion, as well as in the donor pack., Results: Median (range) age at transfusion was 18 (14-39) days with the pretransfusion hemoglobin level at 9.8 (7.4-10.2) g/dl. Interleukin (IL)-1β (P = 0.01), IL-8 (P = <0.001), tumor necrosis factor-α (P = 0.008), and monocyte chemoattractant protein (P = 0.01) were increased after transfusion. A similar elevation in markers of endothelial activation was seen after transfusion with increased plasma macrophage inhibitory factor (P = 0.005) and soluble intracellular adhesion molecule-1 (P = <0.001)., Conclusion: Production of inflammatory cytokines and immunoactivation of the endothelium observed after the transfusion of PRBCs in the preterm infant may be a manifestation of TRIM. The implications of this emerging phenomenon within the preterm neonatal population warrant further investigation.

Objective: We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model., Methods and Results: One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1:1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%, P<0.001, n=9 group), neointimal thickness (51%, P<0.001), stenosis area (37%, P<0.001), and inflammatory score (40%, P<0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%, P<0.05; n=6 group) and monocyte/macrophage content (by 55%, P<0.01; n=5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (P<0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10-300 μmol/L) reduced tumor necrosis factor-α (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production., Conclusion: Our results show the efficacy of bindarit in the prevention of porcine in-stent stenosis and support further investigation for clinical application of this compound.

Monocyte chemoattractant proteins (MCP-1 and MCP-2) mediate monocyte and T-lymphocyte chemotaxis, and IL-1 contributes to the pathogenesis of chorioamnionitis-induced lung inflammation and fetal inflammatory responses. We tested the hypothesis that IL-1 mediates the systemic and pulmonary induction of MCP-1 and MCP-2 in response to lipopolysaccharide (LPS)-induced chorioamnionitis. MCP-1 mRNA, MCP-2 mRNA, and MCP-1 protein expression were measured in two models: 1) intra-amniotic LPS and 2) intra-amniotic recombinant sheep IL-1alpha given at varying intervals before preterm delivery at 124 d GA. Intra-amniotic LPS or IL-1alpha induced MCP-1 mRNA and protein and MCP-2 mRNA in fetal lung many fold at 1-2 d. LPS induced intense MCP-1 expression in subepithelial mesenchymal cells and interstitial inflammatory cells in the lung. Inhibition of IL-1 signaling with recombinant human IL-1 receptor antagonist (rhIL-1ra) did not attenuate LPS induced increase in MCP-1 or MCP-2 expression. MCP-1 and MCP-2 were not induced in liver or chorioamnion, but MCP-1 increased in cord plasma. LPS or IL-1 can induce robust expression of MCP-1 or MCP-2 in the fetal lung. LPS induction of MCP-1 is not IL-1 dependent in fetal sheep. MCP-1 and MCP-2 may be significant contributors to fetal inflammation.

Aims: Several studies suggest a pro-atherogenic role for the CC chemokine receptor 2 (CCR2), thought to reflect interaction with monocyte chemoattractant protein (MCP)-1. Based on its ability to attract leucocytes into inflamed tissue, we hypothesized a pro-atherogenic role for MCP-4, another CCR2 ligand., Methods and Results: Our main findings were: (i) patients with symptomatic carotid stenosis (n = 29), but not those with asymptomatic plaques (n = 31), had significantly raised plasma levels of MCP-4 compared with healthy controls (n = 20); (ii) in vitro, releasate from activated platelets markedly increased the expression of MCP-4 and CCR2 in THP-1 monocytes, and enhanced the MCP-4-mediated effect on interleukin-8 secretion in these cells, involving the platelet-derived chemokine RANTES; (iii) while MCP-1 had no effect on the release of RANTES and interferon-inducible protein of 10 kDa in tumour necrosis factor alpha-pre-activated THP-1 monocytes, MCP-4 profoundly enhanced the release of these pro-atherogenic chemokines; and (iv) the data indicate an inflammatory interaction between RANTES and MCP-4, involving CCR2, and mRNA levels of these mediators were markedly up-regulated within symptomatic atherosclerotic carotid plaque (n = 81)., Conclusion: Our findings suggest that the pro-atherogenic effects of CCR2 may not be restricted to interaction with MCP-1, but could also involve activation by MCP-4, being an inflammatory link between platelet and monocyte activation.

Chronic obstructive pulmonary disease (COPD) is considered an inflammatory pulmonary disorder with systemic inflammatory manifestations. The aim of this study was to assess the systemic levels of six inflammatory mediators in a large cohort of COPD patients and controls. 409 COPD patients and 231 healthy subjects, aged 40-75 yrs, were included from the first phase of the Bergen COPD Cohort Study. All COPD patients were clinically diagnosed by a physician, and had a forced expiratory volume in 1 s/forced vital capacity ratio less than 0.7 and a smoking history of >10 pack-yrs. The plasma levels of C-reactive protein (CRP), soluble tumour necrosis factor receptor (sTNFR)-1, osteoprotegrin, neutrophil activating peptide-2, CXCL16 and monocyte chemoattractant protein-4 were determined by ELISA. After adjustment for all known confounders, COPD patients had significantly lower levels of osteoprotegrin than subjects without COPD (p<0.05), and higher levels of CRP (p<0.01). Among COPD patients, CRP was elevated in patients with frequent exacerbations (p<0.05). sTNFR-1 and osteoprotegrin were both related to Global Initiative for Chronic Obstructive Lung Disease stage and frequency of exacerbations in the last 12 months (p<0.05). In addition, sTNFR-1 was significantly associated with important comorbidities such as hypertension and depression (p<0.05). The present study confirms that certain circulating inflammatory mediators are an important phenotypic feature of COPD.

Rationale: No effective treatment exists for idiopathic pulmonary fibrosis, and its pathogenesis remains unclear. Accumulating evidence implicates herpesviruses as cofactors (either initiating or exacerbating agents) of fibrotic lung disease, but a role for latent herpesvirus infection has not been studied., Objectives: To develop a murine model to determine whether latent herpesvirus infection can augment fibrotic responses and to gain insight into potential mechanisms of enhanced fibrogenesis., Methods: Mice were infected with murine gammaherpesvirus 14 to 70 days before a fibrotic challenge with fluorescein isothiocyanate or bleomycin so that the virus was latent at the time of fibrotic challenge. Measurements were made after viral infection alone or after the establishment of fibrosis., Measurements and Main Results: gammaHerpesvirus is latent by 14 days post infection, and infection 14 to 70 days before fibrotic challenge augmented fibrosis. Fibrotic augmentation was not dependent on reactivation of the latent virus to a lytic state. Total cell numbers and fibrocyte numbers were increased in the lungs of latently infected mice administered fibrotic challenge compared with mock-infected mice that received fibrotic challenge. Latent infection up-regulates expression of proinflammatory chemokines, transforming growth factor-beta1, and cysteinyl leukotrienes in alveolar epithelial cells., Conclusions: Latent gammaherpesvirus infection augments subsequent fibrotic responses in mice. Enhanced fibrosis is associated with the induction of profibrotic factors and the recruitment of fibrocytes. Our data complement existing human and animal data supporting the hypothesis that gammaherpesviruses can serve as initiating cofactors in the pathogenesis of pulmonary fibrosis.

A monocyte-chemoattracting factor is generated during blood coagulation and during clotting of platelet-rich plasma. This chemotactic factor attracts monocytes as a ligand of the C5a receptor; however, it inhibits C5a-induced neutrophil chemotaxis as an apparent receptor antagonist. The curious dual function of the serum monocyte chemotactic factor resembles that of the cross-linked homodimer of ribosomal protein S19 (RP S19). Indeed, the inactive precursor of the monocyte chemotactic factor was present in plasma, and the precursor molecule and RP S19, as well as the active form and the RP S19 dimer, were indistinguishable in terms of immunological reactivity and molecular size. Coagulation factor XIIIa, plasma transglutaminase, and membrane phosphatidylserine on the activated platelets were required for conversion of the precursor to the active form. In addition, the precursor molecule in plasma could be replaced by wild-type recombinant RP S19 but not by mutant forms of it. These results indicate that a molecule indistinguishable from RP S19 was present in plasma, and that the RP S19-like molecule was converted to the active form by a transglutaminase-catalyzed reaction on a scaffold that included the phosphatidylserine-exposed platelet membrane.

Background: Previous studies suggest that CCL13 may have some role in the pathogenesis of systemic sclerosis (SSc)., Objectives: To determine serum levels of CCL13 and its clinical associations in patients with SSc., Methods: Serum CCL13 levels were examined by enzyme-linked immunosorbent assay in 80 patients with SSc, 20 patients with systemic lupus erythematosus (SLE), 20 patients with dermatomyositis (DM), 29 patients with atopic dermatitis (AD) and 50 healthy individuals., Results: Mean + or - SD serum CCL13 levels were elevated in patients with SSc (81.3 + or - 55.8 pg mL(-1)) compared with healthy controls (15.0 + or - 9.9 pg mL(-1); P < 0.001) and patients with SLE (22.0 + or - 6.9 pg mL(-1); P < 0.001), DM (24.4 + or - 36.1 pg mL(-1); P < 0.001) and AD (18.0 + or - 6.4 pg mL(-1); P < 0.001). Among patients with SSc, there were no differences in serum CCL13 levels between limited cutaneous SSc and diffuse cutaneous SSc. In a longitudinal study, CCL13 levels were generally unchanged during the follow-up., Conclusions: Serum CCL13 was specifically increased in patients with SSc, but not in patients with SLE, DM or AD or in healthy controls. CCL13 could be a promising serological marker for SSc.

Balb/c mice infected with the gastrointestinal nematode Heligmosomoides bakeri were fed protein sufficient (PS, 24%) or deficient (PD, 3%) diets to investigate whether diet, infection or dose of larval challenge (0, 100 or 200 larvae) influenced gut pathophysiology and inflammation. Among the PS mice, worms were more posteriorad in the intestine of mice infected with 200 compared with 100 larvae, suggesting active expulsion in the more heavily infected mice. This was consistent with the positive correlation between worm numbers and fluid leakage in PS mice; similar patterns were not detected in the PD mice. Infection also induced villus atrophy, which was more pronounced in PS than in PD mice. Our cytokine screening array indicated that infection in PD mice elevated a wide range of pro-inflammatory cytokines and chemokines. Whereas serum leptin concentrations were higher in PD mice, monocyte chemotactic protein-5 (MCP-5) in serum increased with increasing larval dose and concentrations were lower in PD than PS mice. We suggest that elevated MCP-5 together with villus atrophy may contribute to the apparent dose-dependent expulsion of H. bakeri from PS mice but that delayed expulsion in PD mice appeared related to a predominant Th1 cytokine profile that may be driven by leptin.

Background: Bullous pemphigoid (BP) is an autoimmune inflammatory disease causing blister formation at the dermoepidermal junction. Cutaneous infiltration of activated CD4+ T cells and eosinophils is an early event in blister formation during the disease process, suggesting that the trafficking of circulating leucocytes through the sites of inflammation is crucial in the pathogenesis of the disease. While the accumulated evidence suggests that some cytokines are involved in the pathogenesis, there have been few reports about serum chemokine profiles in patients with BP., Objectives: To determine serum profiles of various chemokines and their clinical association in patients with BP., Methods: Concentrations of 10 chemokines - interferon (IFN)-gamma-inducible protein-10 (IP-10), monokine induced by IFN-gamma (MIG), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES, eotaxin, monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3 and growth-regulated oncogene-alpha- were measured in serum samples from 38 patients with BP, 16 with pemphigus vulgaris (PV) and 17 normal controls using a sandwich immunoassay-based multiplex protein array system., Results: While there was no significant increase in any serum chemokine levels in patients with PV, serum levels of IP-10 and MCP-1 were significantly increased in patients with BP compared with healthy controls. Furthermore, serum levels of IP-10, MIG, MCP-1 and eotaxin in patients with BP increased significantly with disease severity as determined by the area affected., Conclusions: These observations suggest that an elaborately orchestrated network of chemokines, especially MCP-1 and IP-10, contributes to the pathomechanism of BP.

Objective: Chronic inflammation observed in obesity has been reported to be implicated in the development of atherosclerosis. We screened candidate chemokines that link chronic inflammation and obesity., Research Methods and Procedures: Japanese overweight (n = 39, BMI 28.7 +/- 0.65 kg/m(2)) and normal-weight (n = 24, BMI 22.3 +/- 0.45 kg/m(2)) subjects were enrolled. Using antibody-based protein microarray, spot intensities of monocyte chemoattractant protein (MCP)-4, eotaxin, and eotaxin-2 correlated with anthropometric parameters. We further measured serum concentration of these chemokines and mRNA levels in adipose tissues obtained from volunteers., Results: Serum MCP-4 levels showed positive correlation with BMI (r = 0.318, p = 0.014), waist (r = 0.316, p = 0.018), and waist-to-hip ratio (WHR) (r = 0.264, p = 0.049). Furthermore, MCP-4 correlated with homeostasis model assessment of insulin resistance (r = 0.392, p = 0.002), high-sensitivity C-reactive protein (hsCRP) (r = 0.350, p = 0.006). In step-wise multiple regression analyses, hsCRP independently correlated with MCP-4 levels. The expression of MCP-4 mRNA in visceral adipose tissue positively correlates with BMI. Serum eotaxin levels correlate with BMI (r = 0.262, p = 0.045) and WHR (r = 0.383, p = 0.003). Serum eotaxin-2 levels correlated with BMI (r = 0.464, p < 0.001), waist (r = 0.333, p = 0.017), and WHR (r = 0.278, p = 0.048). However, eotaxin and eotaxin-2 levels did not show significant correlation with hsCRP., Discussion: Serum levels of MCP-4, eotaxin, and eotaxin-2, which belong to CC chemokine family and share CC chemokine receptor 3, correlated with BMI. These chemokines, especially MCP-4, may be critical molecules that link obesity and chronic inflammation.

Objectives: To study the role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 in the pathogenesis of rheumatoid arthritis (RA), we analysed the expression of MCP-4/CCL13 in chondrocytes, synovial fluid and serum from patients with RA and investigated the effect of MCP-4/CCL13 on the proliferation of synovial cells., Methods: Human articular cartilage specimens were obtained from joints from RA and osteoarthritis (OA) patients and normal joints (controls). Transcript levels of MCP-4 in cartilage were determined by real-time polymerase chain reaction. Protein levels were measured by enzyme-linked immunoassay. Cultured fibroblast-like synoviocytes (FLS) were treated with various concentrations of recombinant MCP-4/CCL13 protein, and cell proliferation was evaluated with a viability assay., Results: The gene expression of MCP-4 was significantly higher in cartilage from RA patients than in that from OA patients (P = 0.00902) and in normal cartilage (P = 0.00902). The concentration of MCP-4/CCL13 protein in serum from RA patients (mean 94.7 +/- 37.6 pg/ml) was significantly higher than in serum from OA patients (mean 49.2 +/- 31.2 pg/ml, P = 0.0051) and controls (mean 32.6 +/- 23.9 pg/ml, P = 0.0001). The concentration of MCP-4/CCL13 protein in synovial fluid from RA patients (mean 247.2 +/- 161.2 pg/ml) was also significantly higher than in that from OA patients (mean 29.6 +/- 50.5 pg/ml, P = 0.000019). Moreover, MCP-4/CCL13 enhanced the proliferation of FLS in a dose-dependent manner., Conclusions: MCP-4/CCL13 is highly expressed in RA joints at the mRNA and protein levels. Our results suggest that MCP-4/CCL13 is secreted from chondrocytes and activates the proliferation of rheumatoid synovial cells, thereby leading to joint destruction in RA.

Objective: To determine serum levels of monocyte chemotactic protein-3 (MCP-3) and its clinical associations in patients with systemic sclerosis (SSc)., Methods: Serum MCP-3 levels from 69 patients with SSc were examined by ELISA., Results: Serum MCP-3 levels were raised in patients with SSc (n = 69) compared with healthy controls (n = 28). Patients with diffuse cutaneous SSc (n = 36) had higher levels of serum MCP-3 than those with limited cutaneous SSc (n = 33). Patients with raised MCP-3 levels had pulmonary fibrosis and decreased vital capacity (VC) more often than those with normal MCP-3 levels. MCP-3 levels correlated positively with the extent of skin fibrosis, and inversely with %VC and carbon monoxide transfer factor (Tlco) in patients with SSc., Conclusion: MCP-3 levels were increased in patients with SSc, and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that MCP-3 may have a role in the development of fibrosis in SSc.

Background: Tuberculosis causes 3 million deaths annually. The most common site of tuberculosis is pulmonary however; extra-pulmonary forms of the disease also remain prevalent. Restriction of Mycobacterium tuberculosis depends on effective recruitment and subsequent activation of T lymphocytes, mononuclear and polymorphonuclear cells to the site of infection. Tumor necrosis factor (TNF)-alpha is essential for granuloma formation and is a potent activator of monocyte chemotactic protein (MCP-1, CCL2). CCL2 is essential for recruitment of monocytes and T cells and has been shown to play a role in protection against tuberculosis. Interleukin -8 (CXCL8) is a potent activator of neutrophils. Increased levels of CCL2, CXCL8 and TNFalpha are reported in tuberculosis but their significance in different forms of tuberculosis is as yet unclear. We have used an ex vivo assay to investigate differences in immune parameters in patients with either pulmonary or extra-pulmonary tuberculosis., Methods: Serum levels of CCL2, CXCL8 and TNFalpha were measured in patients with pulmonary tuberculosis (N = 12), extra-pulmonary tuberculosis (N = 8) and BCG-vaccinated healthy volunteers (N = 12). Whole blood cells were stimulated with non-pathogenic Mycobacterium bovis bacille-Calmette Guerin (BCG) vaccine strain or bacterial lipopolysaccharide (LPS) and cyto/chemokines were monitored in supernatants., Results: Circulating serum levels of CXCL8 and TNFalpha were raised in all tuberculosis patients, while CCL2 levels were not. There was no difference in spontaneous cytokine secretion from whole blood cells between patients and controls. M. bovis BCG-induced ex vivo CCL2 secretion was significantly greater in pulmonary as compared with both extra-pulmonary tuberculosis patients and endemic controls. In response to LPS stimulation, patients with pulmonary tuberculosis showed increased CCL2 and TNFalpha responses as compared with the extra-pulmonary group. BCG-, and LPS-induced CXCL8 secretion was comparable between patients and controls., Conclusion: CCL2 is activated by TNFalpha and is essential for recruitment of monocytes and T cells to the site of mycobacterial infection. Increased CCL2 activation in pulmonary tuberculosis may result in a stronger cellular response as compared with extra-pulmonary tuberculosis patients, and this may contribute to the localization of infection to the pulmonary site.

Airway expression of monocyte chemotactic protein-4 (MCP-4; CCL-13) is known to be increased in asthmatic airways where it is induced by proallergic cytokines, but the relationship of its systemic expression to asthma and naturally occurring exacerbations is unknown. We determined plasma levels of MCP-4 in 356 individuals with chronic-stable asthma and 240 normal subjects and compared plasma levels of MCP-4 in 30 patients who presented for emergent treatment of asthma with levels in 90 subjects with chronic-stable asthma matched for age, gender, and ethnicity. Median plasma MCP-4 levels were higher in patients with chronic-stable asthma than in normal subjects (399 vs. 307 pg/mL) (p < 0.001). In our entire cohort (n = 596), subjects with an MCP-4 > 218 pg/mL were at increased risk of asthma (p < 0.001 odds ratio, 3.26; 95% CI, 2.22-4.79). Logistic regression identified MCP-4 as an independent predictor of asthma diagnosis. The MCP-4 levels are higher in individuals with an acute asthma exacerbation than in subjects with chronic-stable asthma (513 vs. 355 pg/mL) (p = 0.002). The MCP-4 is a systemically expressed biomarker that independently predicts susceptibility to asthma and is directly associated with exacerbations. Elevated MCP-4 levels identify a group of asthmatics with systemic evidence of allergic inflammation who may be at risk for exacerbations or may benefit from abrogation of MCP-4.

Monocyte chemoattractant protein-4 (MCP-4) is a CC chemokine implicated in the recruitment of eosinophils, monocytes, and T-lymphocytes in diseases of mucosal inflammation, including asthma. We tested the hypothesis that there is a genetic basis for differences in MCP-4 expression among individuals by evaluating the effects of core promoter variants on MCP-4 expression. We identified two single-nucleotide T-to-C polymorphisms in the MCP-4 core promoter that occur 896 and 887 base pairs preceding the transcription initiation site. The -887 variant alters a consensus binding motif for the transcription factor YY-1. Electrophoretic mobility shift assay demonstrated that YY-1 containing nuclear extracts from tumor necrosis factor-alpha-stimulated peripheral blood mononuclear cells had greater avidity for the wild-type (YY-1 motif intact) sequence than for the variant sequence. Increasing doses of a YY-1 expression vector induced significantly greater reporter activity from MCP-4 core promoter expression constructs of the wild-type compared with the variant sequence in transient transfection experiments. The external validity of these observations was demonstrated by measuring plasma levels of MCP-4 from individuals with the alternative forms of the gene. Individuals bearing haplotypic variants of the MCP-4 core promoter that avidly bind the transcription factor YY-1 had higher plasma levels of MCP-4 than did individuals with variants with lower binding avidity (490, 360, and 360 pg/ml; P < 0.01). Our findings suggest that the MCP-4 core promoter YY-1 binding motif is functional, modulates the transcriptional regulation of the MCP-4 gene, and that part of the variance in the systemic expression of MCP-4 is determined by core promoter genetic variants.

Objectives: Glucose metabolism disorders usually coexist with dyslipidemia and coagulation/fibrinolysis disturbances. Increase of insulin resistance followed by hyperinsulinemia leads to enhanced protein synthesis, including production of apolipoproteins. As a result, the structure of Low Density Lipoprotein (LDL) becomes small and dense. This augments lipid infiltration into the arterial wall. Following this process monocyte adhesion to endothelium initiates atherosclerotic injury. One of the markers of this inflammatory reaction is Monocyte Chemoattractant Peptide-1 (MCP-1). A lot of inflammatory mediators affect both oxidative modification of LDL and coagulation processes being responsible for anti-fibrinolytic predominance. Plasminogen Activator Inhibitor-1 (PAI-1) is a marker of this state. Therefore the aim of this study is to evaluate the marker of the oxidation processes (oxLDL) as well as prothrombotic (PAI-1) and inflammatory state (MCP-1) markers in patients with Impaired Glucose Tolerance (IGT)., Methods: The study was carried out on 16 subjects: 10 with biochemically confirmed IGT and 6 age-matched healthy persons without such disorders. Following tests were performed: OGTT, HbA(1c) level as well as TCh, HDL, LDL and TG. Plasma concentrations of oxLDL, PAI-1 and MCP-1 were measured using ELISA method., Results: In patients with Impaired Glucose Tolerance plasma levels of oxLDL were significantly higher compared to control group (67.6 +/- 0.9 U/l vs. 57.8 +/- 4.0 U/l; p < 0.01) in spite of LDL levels, which did not reveal such difference. MCP-1 plasma concentration compared to control group occurred to be significantly increased in experimental group as well (156.4 +/- 9.2 ng/ml vs. 125.4 +/- 1.9 ng/ml; p < 0.05). PAI-1 level revealed most significant difference (84.0 +/- 1.8 ng/ml vs. 43.7 +/- 2.7 ng/ml; p < 0.0001)., Conclusions: It is concluded that patients with Impaired Glucose Tolerance should be considered as a group in which atherogenic modification of lipoproteins occurred. Also plasma inflammatory as well as prothrombotic markers concentration was elevated.

Acute graft-versus-host disease (GVHD) involves mainly skin, liver and intestines. Other organs such as heart, muscle and central nervous system are seldom affected, although their parenchymal cells also express alloantigens, such as MHC class I antigens. The mechanism of this selective involvement of distinct organs in acute GVHD is not well understood. We postulated that it might be related to the selective migration of activated alloreactive T cells. Indeed, T cell infiltration, revealed by examination of serial samples using flow cytometry and immunohistology, occurred early and continuously in the target organs such as the liver, but not in a non-target organ, the heart, in a murine acute GVHD model. Since T cell migration is largely controlled by the expression of chemokine and chemokine receptors, we investigated the chemokine spectrum in target/non-target organs of mice with acute GVHD. We found that in the spleen and liver MIP-1alpha, MIP-2 and Mig were the predominant chemokines expressed. In another target organ, the skin, MIP-1alpha, MIP-2, MCP-1 and MCP-3 were all highly expressed. In a non-target organ of acute GVHD, the heart, the predominant chemokines expressed were MCP-1 and MCP-3. This distinct pattern of chemokine expression in these organs may contribute to the preferential recruitment of inflammatory cells into the liver and skin, but not into the heart, in acute GVHD.

Synovial tissues from Rheumatoid Arthritis (RA) were divided into three groups based on their histopathological findings and compared for their expression of IL-8 and monocyte chemotactic and activating factor (MCAF) by using immunohistochemistry and in situ hybridization. The levels of IL-8 as well as those of MCAF were markedly higher in the synovial fluid from RA joints. Synovial lining cells (SLC) and macrophages had an ability to produce IL-8 at an early phase of the disease. The presence of MCAF was restricted in macrophages at this stage. On the other hand, the production of IL-8 as well as MCAF were prominent in most components of the joints such as SLC, migrated monocytes, sublining fibroblastoid cells, endothelial cells or migrated neutrophils at an active phase. The expression of IL-8 or MCAF was low in fibrotic synovitis of RA. These data indicate that IL-8 generated from SLC and macrophages may participate to the inflammatory process in the early synovitis of RA.

Intravenous injection of sublethal or lethal doses of Escherichia coli in baboons resulted in increased serum levels of the matrix metalloprotease gelatinase B and the chemokine monocyte chemotactic protein 2 (MCP-2). In both animal models, gelatinase B appeared faster than MCP-2. After sublethal challenge, serum levels of gelatinase B and MCP-2 were found to be correlated, reaching peak levels between 2 and 4 h after bacterial challenge. After lethal challenge, however, MCP-2 tended to increase until 10 h. The kinetics of appearance suggest induction of release of gelatinase B and de novo synthesis and secretion of MCP-2, both by endotoxin.

The present study examined whether maternal serum cytokine levels are useful for the diagnosis of histologic chorioamnionitis. The blood samples of 29 women who delivered preterm between 22 and 34 weeks of gestation were collected at delivery, and placentas were histopathologically examined for chorioamnionitis. The interleukin (IL) 6 titer was higher in 18 mothers with histologic chorioamnionitis (median 12.0 pg/ml, range 4.9-63.5 pg/ml) than that in 11 mothers without histologic chorioamnionitis (median 3.5 pg/ml, range 1.7-14.9 pg/ml; p < 0.0001). The C-reactive protein (CRP) titer also differed significantly between these two groups (chorioamnionitis group: median 5.2 mg/dl, range 0.1-12.3 mg/dl; no chorioamnionitis group: median 0.2 mg/dl, range 0.1-0.5 mg/dl; p = 0.0001). The IL-6 titer showed better clinical diagnostic indices and a higher odds ratio (9.78, 95% confidence interval 1.50-63.82) than did CRP (3.26, 95% confidence interval 1.22-8.67). The levels of IL-8, monocyte chemotactic and activating factor, and soluble IL-6 receptor did not differ between the two groups. These data suggest that the level of maternal serum IL-6 is more useful than other markers, including CRP, for the identification of women at risk of impending preterm labor with histologic chorioamnionitis.

Histamine-releasing factor (HRF) consists of a group of cytokines that can cause basophil/mast cell to release histamine, however, the composition of HRF still remains undefined. This study was designed to measure the concentrations of chemokines in asthmatic children receiving immunotherapy. Peripheral blood mononuclear cells culture supernatants were obtained from six asthmatic children before and four, eight months after immunotherapy (IT). The levels of monocyte chemotactic and activating factor (MCAF), macrophage inflammatory protein-1a (MIP-1a), regulated on activation normal T-cell expressed and secreted (RANTES) and interleukin-8 (IL-8) spontaneously and after stimulation with PHA and mite allergen in the supernatants. The data showed: 1) The levels of MCAF and MIP-1a increased four months, and decreased eight months, after IT; 2) By contrast, the level of RANTE increased after IT; 3) The level of IL-8 also tended to increase after IT. Abnormal chemokine production may contribute to the pathogenesis of bronchial asthma and restoration of normal chemokine production may be used to partially explain the clinical efficacy of immunotherapy.

Because of their effects on monocytes, monocyte chemotactic proteins-1 and -2 (MCP-1 and MCP-2) may participate in the pathophysiology of sepsis. We measured circulating MCP-1 and MCP-2 levels in 42 septic patients having positive local or blood cultures. MCP-1 and MCP-2 levels were elevated in 24 (57%) and 25 (59%) of 42 septic patients, respectively, compared with healthy volunteers. Both patients with gram-positive and gram-negative infections had elevated MCP-1 plasma levels (P = .0001) and P < .0001), respectively; Mann-Whitney-U test), whereas patients with gram-positive infection, but not those with gram-negative infection, had increased MCP-2 plasma levels (P= .0182). No relative differences in MCP-1 and MCP-2 plasma levels were observed between several subgroups of patients (sepsis v septic shock; survivors v nonsurvivors), although levels of MCP-1 were the highest in patients with the more severe forms of sepsis, ie, those with shock or a lethal outcome. Serial observations showed that MCP-1 and MCP-2 plasma levels remained elevated for at least 48 hours. MCP-1 correlated weakly with interleukin-8 and MCP-2, the correlations for which were most pronounced in patients with septic shock. MCP-2 correlated with interleukin-8, and surprisingly, with the complement activation product C3a; these correlations further improved when analyzing patients with septic shock or when applying gram-positive infections. Thus, our results not only show increased MCP-1 and MCP-2 levels in patients with sepsis, but also suggest that the synthesis and release of MCP-1 and MCP-2 in sepsis are differently regulated in part.

Proinflammatory cytokines have been implicated in mediating tissue injury after cardiopulmonary bypass. Causative factors of inflammatory response after cardiopulmonary bypass include contact of the blood with the extracorporeal circuit and heart-lung reperfusion injury when discontinuing bypass. To evaluate proinflammatory cytokine release during cardiopulmonary bypass, plasma levels of interleukin-6, 8, and monocyte chemoattractant factor were measured in the radial artery (for systemic blood) and left atrium before and after cardiopulmonary bypass. A total of 13 patients were studied, with no deaths or complications. In both radial artery and left atrium, interleukin-6, 8, and monocyte chemoattractant factor rose significantly after cardiopulmonary bypass (p < 0.05 versus before cardiopulmonary bypass). These changes may have been caused by removal of the aortic cross clamp and recommencement of artificial ventilation, which result in reperfusion of the pulmonary capillary beds. There were no differences in cytokine levels after cardiopulmonary bypass in the radial artery and left atrium. This result suggested that lung reperfusion injury after cardiopulmonary bypass may not be the major causative factor of the release of proinflammatory cytokines.