CCL2 In Patients Research Articles

High Serum Levels of CXC (CXCL10) and CC (CCL2) Chemokines in Untreated Essential Hypertension

Hypertension has been suggested to exert pro-inflammatory actions through increased expression of several mediators, including chemokines. Chemokines are involved in inflammatory and autoimmune disorders, and in the formation of atherosclerotic lesions through promotion of inflammatory cell migration. The aim of this study is to evaluate the influence of high blood pressure on circulating levels of the prototype chemokines C-X-C motif ligand (CXCL)10 and C-C motif ligand (CCL)2 in 140 patients with essential hypertension not affected by thyroid disorders or overt autoimmune or inflammatory diseases, and 140 gender- and age-matched healthy controls. Mean CXCL10 and CCL2 levels were significantly higher in hypertensive patients than in controls. Among hypertensive patients, chemokines levels were higher in those with systo-diastolic hypertension compared to those with isolated systolic hypertension. In a multiple linear regression model using CXCL10 or CCL2 as dependent variables and age, body mass index, glycemia, serum creatinine, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, triglycerides, and systolic or diastolic blood pressure values as covariates, only systolic or diastolic blood pressure values were significantly related to CXCL10 or CCL2 levels. In conclusion, this study demonstrates increased circulating levels of the prototype chemokines CXCL10 and CCL2 in patients with hypertension.

High Expression of CCL20 Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma after Curative Resection

IntroductionChemokine ligand 20 (CCL20) plays an important role in the carcinogenesis, invasion, and progression of malignancies. This study aimed to investigate the prognostic significance of CCL20 in patients with hepatocellular carcinoma (HCC) after curative resection. MethodsExpression of CCL20 was evaluated by immunohistochemistry in tumor tissue from 125 patients who underwent curative resection of HCC. The relationship between CCL20 expression and clinicopathologic features was analyzed. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of HCC patients. ResultsCCL20 expression was verified in all tumor specimens. CCL20 expression was associated with tumor size (P = 0.002), tumor number (P = 0.031), vascular invasion (P = 0.003), tumor differentiation (P = 0.024), and tumor recurrence (P < 0.001). Patients with high CCL20 expression had poorer recurrence-free survival and overall survival (both P < 0.001) than those with low CCL20 expression. Multivariate analysis showed CCL20 expression was an independent predictor of tumor recurrence (Hazard ratio 3.934, P = 0.002), recurrence-free survival (Hazard ratio 2.573, P = 0.001), and overall survival (Hazard ratio 2.930, P = 0.001). ConclusionCCL20 expression was associated with tumor recurrence and survival of HCC patients. It may be used to predict prognosis of patients with HCC and may be a new target of postoperative adjuvant therapy.

Chemokine saliva levels in patients with primary Sjogren's syndrome, associated Sjogren's syndrome, pre-clinical Sjogren's syndrome and systemic autoimmune diseases

To assess the saliva levels of CXCL13, CXCL10, CCL2, CCL3, CXCL12 and CCL5 in patients with primary SS (pSS), patients with associated SS (aSS), patients with systemic autoimmune disease (SAD) without SS, pre-clinical SS and healthy controls. We included 44 patients with pSS (Group A), 30 with aSS (Group B), 49 with SAD without SS (Group C), 14 patients with SAD and focal lip infiltrates, but who do not fulfil SS criteria (Group D, pre-clinical SS) and 32 healthy controls (Group E). Saliva samples were collected and analysed for chemokine levels by luminometry. We used descriptive statistics and the Mann-Whitney U-test and Kruskall-Wallis test. All the studied chemokines were found at low concentration in controls with the exception of CCL2. Patients with pSS had higher levels CXCL10 and CCL2 than controls (P = 0.05). However, they had similar levels of CXCL13, CCL5, CXCL12, CCL2 and CXCL10 than patients with aSS and SAD without SS. Patients with pre-clinical SS had higher levels of CXCL10 than patients with pSS (P = 0.03), aSS (P = 0.04) and controls (P = 0.001). CCL2 levels were higher in all patients with an autoimmune background when compared with controls (P < 0.05 for each comparison). We found no difference in salivary chemokines between patients neither with pSS or aSS nor in patients with SAD. CCL2 and CXCL10 were increased in all patients with an autoimmune background. CXCL10 was notably increased in pre-clinical SS, suggesting it could be an early inflammatory salivary biomarker.

CXCL10 and CCL2 Chemokine Serum Levels in Patients With Hepatitis C Associated With Autoimmune Thyroiditis

To evaluate CXCL10 and CCL2 in patients with hepatitis C virus chronic infection in presence/absence of autoimmune thyroiditis (AT). CXCL10 was significantly higher in: (1) patients with AT than controls without AT (control 1) (P < 0.001; ANOVA); (2) patients with hepatitis C infection than control 1 and patients with AT (P < 0.001); (3) patients with hepatitis C virus chronic infection and AT (HCV+AT) than control 1 and patients with AT (P < 0.001) and hepatitis C (P = 0.004). By defining a high CXCL10 level as a value >218 pg/mL, 2% of control 1, 14% of patients with AT, 68% of patients with hepatitis C infection, 81% of HCV+AT had high CXCL10 (P < 0.0001; chi-square). CCL2 was similar in control 1 and patients with AT. CCL2 was significantly higher in: (1) patients with hepatitis C infection than control 1 (P = 0.04; ANOVA); (2) HCV+AT than patients with AT (P = 0.03) and control 1 (P = 0.02); no difference was observed between HCV with or without AT. Our study demonstrates: (1) higher circulating CXCL10 and CCL2 in patients with hepatitis C virus chronic infection than in controls; (2) higher CXCL10 in HCV+AT than in patients with hepatitis C infection, suggesting a stronger Th1 immune response in these patients.

α-Chemokine CXCL10 and β-chemokine CCL2 serum levels in patients with hepatitis C–associated cryoglobulinemia in the presence or absence of autoimmune thyroiditis

Chemokines have been identified to play an important role in endocrine autoimmune disease and hepatitis C chronic infection. To our knowledge, no study has evaluated serum levels of CXCL10 and CCL2 in patients with “mixed cryoglobulinemia and hepatitis C virus chronic infection” (MC) in the presence or absence of autoimmune thyroiditis (AT). Serum CXCL10 and CCL2 were assayed in 60 patients with MC, in 45 patients with “MC with AT” (MC + AT), and in controls (60 without [control 1] and 45 with AT [control 2]). CXCL10 was significantly higher (1) in control 2 than in control 1 ( P < .001), (2) in MC than in control 1, and (3) in MC + AT than in controls 1 and 2 and in MC ( P = .002). A high CXCL10 level (>mean + SD control 1; >167 pg/mL) was present in 7% control 1, 21% control 2, 49% MC, and 78% MC + AT ( P < .0001). CCL2 was significantly higher in MC and in MC + AT than in control 1 or in control 2 ( P < .01). A high CCL2 level (>mean + SD control 1; >730 pg/mL) was present in 2% control 1, 1% control 2, 18% MC, and 21% MC + AT ( P < .0001). The study demonstrates high CXCL10 and CCL2 serum levels in patients with MC; CXCL10 in MC + AT is significantly higher than that in MC. Future studies in larger series will be needed to evaluate the potential usefulness of serum CXCL10 and CCL2 determination as a prognostic marker in the follow-up of MC patients, also in relation to the presence of AT.

Increased expression of CC chemokine ligand 18 in extrinsic atopic dermatitis patients

Background: Although most patients with atopic dermatitis (AD) show high total and allergen‐specific serum immunoglobulin E (IgE) levels, a small subgroup of AD patients have normal total IgE levels and negative serum allergen‐specific IgE. This subgroup has been termed ‘intrinsic’ AD (IAD) as a counterpart to ‘extrinsic’ AD (EAD). However, the difference of chemokines between IAD and EAD has not yet been evaluated.Objective: We investigated the expression of CC chemokine ligand (CCL) 17, CCL22, and CCL18 in patients with IAD and EAD, which are known to be highly expressed in AD patients.Methods: We assessed the protein levels of these chemokines in peripheral blood mononuclear cells (PBMCs), sera and lesional skins. We also evaluated CCL18 mRNA levels in monocytes, Langerhans cell (LC)‐like dendritic cells (DCs) and inflammatory dendritic epidermal cell (IDEC)‐like DCs from both types of AD patients.Results: There were no significant differences in CCL17 and CCL22 expression in PBMCs, sera and lesional skins of patients with IAD and EAD. CCL18 expression did not differ in PBMCs, sera and LC‐like DCs from the two subgroups, but strong CCL18 expression was observed in lesional skins and IDEC‐like DCs in patients with EAD. Lastly, serum CCL18 levels significantly decreased after immunotherapy.Conclusion: This study suggests that the chemokine micromilieu, especially the level of CCL18, is different between EAD and IAD patients. High FcεRI surface‐expressing DCs, such as IDEC, were the major source of CCL18, and produced a prominent CCL18 microenvironment in EAD patients compared with IAD patients.

Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy

Cytokine-induced inflammation is involved in the pathogenesis of type 2 diabetes mellitus (DM). We investigated plasma concentrations and ex vivo production of cytokines and chemokines, and intracellular signalling molecules, mitogen-activated protein kinases (MAPK) in T helper (Th) cells and monocytes in 94 type 2 diabetic patients with or without nephropathy and 20 healthy controls. Plasma concentrations of inflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-18 and chemokine CCL2 in patients with diabetic nephropathy (DN) were significantly higher than control subjects, while IL-10, CXCL8, CXCL9, CXCL10 and adiponectin concentrations of DN were significantly higher than patients without diabetic nephropathy (NDN) and control subjects (all P < 0.05). Plasma concentrations of TNF-alpha, IL-6, IL-10, IL-18, CCL2, CXCL8, CXCL9, CXCL10 and adiponectin exhibited significant positive correlation with urine albumin : creatinine ratio in DN patients. The percentage increases of ex vivo production of IL-6, CXCL8, CXCL10, CCL2 and CCL5 upon TNF-alpha activation were significantly higher in both NDN and DN patients than controls (all P < 0.05). The percentage increases in IL-18-induced phosphorylation of extracellular signal-regulated kinase (ERK) in Th cells of NDN and DN were significantly higher than controls (P < 0.05), while the percentage increase in TNF-alpha-induced phosphorylation of p38 MAPK in monocytes and IL-18-induced phosphorylation of p38 MAPK in Th cells and monocytes were significantly higher in NDN patients than controls. These results confirmed that the aberrant production of inflammatory cytokines and chemokines and differential activation of MAPK in different leucocytes are the underlying immunopathological mechanisms of type 2 DM patients with DN.

Chemokine Complexity

William of Ockham (of Ockham's Razor fame) and Albert Einstein both urged us to keep it simple, but biology, perhaps in comparison to philosophy or physics, is often a more complicated matrix. An example of the complex nature of nature is the case of chemokine action in mediating inflammatory disease. Thus, chemokines were associated initially with the development of inflammatory and allergic disease primarily through their role as chemoattractant cytokines. In turn, increased lung levels of the chemokine CCL5 in patients with asthma and in mouse models of asthma (1, 2) were presumed to cause further recruitment of inflammatory cells, especially eosinophils, into airway tissue and consequent worsening of airway disease. However, this view of CCL5, and chemokines in general, turns out to be quite naive, as underscored by an additional article in the current issue of the AJRCMB (3). In this new article, Koya and colleagues (pp 147–154) show that CCL5 selectively dampens the long-term effect of allergen challenge in mice (3). In this model, prolonged allergen exposure (out to 48 d after initial sensitization) led to airway hyperreactivity and mucous cell metaplasia, and administration of CCL5 decreased these traits, whereas treatment with anti-CCL5 antibody significantly increased them. Administration of CCL5 also caused an increase while anti-CCL5 antibody caused a decrease in BAL fluid levels of IFN-γ as well as IFN-γ-producing CD4 T cells. Moreover, anti–IFN-γ antibody treatment caused an increase in airway hyperreactivity. Together, the results suggest that CCL5 somehow stimulates the generation of IFN-γ–producing Th1 cells that protect against a prolonged allergic response. Whether concomitant changes in lung IL-12 levels are linked to this mechanism remains uncertain. Similarly, why this action takes place after longer- but not shorter-term allergen exposure still needs to be defined, but presumably relies on the delayed development of an activated Th1 cell population.

Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention

AbstractGaucher disease is characterized by storage of glucosylceramide in lysosomes of tissue macrophages as the result of an autosomal recessively inherited deficiency in glucocerebrosidase. Progressive accumulation of these glycolipid-laden Gaucher cells causes a variety of debilitating symptoms. The disease can be effectively treated by costly intravenous infusions with recombinant glucocerebrosidase. Chitotriosidase is massively secreted by Gaucher cells and its plasma levels are used to monitor efficacy of enzyme therapy. Broad-scale application is hampered by the common genetic defect in this surrogate marker. We report that in plasma of symptomatic patients with Gaucher disease the chemokine CCL18 is on average 29-fold elevated, without overlap between patient and control values (median control plasma level is 33 ng/mL, range, 10-72 ng/mL; median Gaucher plasma level is 948 ng/mL, range, 237-2285 ng/mL). Plasma CCL18 concentrations decrease during therapy, comparably to chitotriosidase levels. Immunohistochemistry demonstrates that Gaucher cells are the prominent source of CCL18. Plasma CCL18 levels can serve as alternative surrogate marker for storage cells in patients with Gaucher disease and monitoring of plasma CCL18 levels proves to be useful in determination of therapeutic efficacy, especially in patients who are deficient in chitotriosidase activity. The potential physiologic consequences of chronically elevated CCL18 in patients with Gaucher disease are discussed.