The advent of effective combination antiretroviral therapy (ART) in 1996 resulted in fewer patients experiencing clinical events， so that some prognostic analyses of individual cohort studies of -infected individuals had low statistical power. Because of this， the Antiretroviral Therapy Cohort Collaboration (ART-CC) of cohort studies in Europe and North America was established in 2000， with the aim of studying the prognosis for clinical events in and the mortality of adult patients treated for . In 2002， the ART-CC collected data on more than 12，000 patients in 13 cohorts who had begun combination ART between 1995 and 2001. Subsequent updates took place in 2004， 2006， 2008， and 2010. The ART-CC data base now includes data on more than 70，000 patients participating in 19 cohorts who began treatment before the end of 2009. Data are collected on patient demographics (e.g. sex， age， assumed transmission group， race/ethnicity， geographical origin)， biomarkers (e.g. cell count， plasma viral load of )， ART regimen， dates and types of events， and dates and causes of . In recent years， additional data on co-such as ; risk factors such as smoking， alcohol and drug use; non-biomarkers such as and liver enzymes; and adherence to ART have been collected whenever available. The data remain the property of the contributing cohorts， whose representatives manage the ART-CC via the steering committee of the Collaboration. External collaboration is welcomed. Details of contacts are given on the ART-CC website (www.art-cohort-collaboration.org).
CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischemic symptoms.
Chemokines play an important role in atherogenesis and in ischemic injury and repair; however， prospective data on individual chemokines in unstable angina pectoris (UAP) are scarce. Therefore， we assessed chemokine patterns in a prospective cohort of patients with UAP.Plasma samples of 54 patients with Braunwald class IIIB UAP were examined at baseline for 11 chemokines and 5 inflammatory mediators via multiplex analysis. Levels of CC chemokine ligand (CCL)-5 (also known as RANTES [regulated on activation， normally T-cell expressed， and secreted]; 32.7 versus 23.1 ng/mL， P=0.018) and CCL18 (also known as PARC [pulmonary and activation-regulated chemokine]; 104.4 versus 53.7 ng/mL， P=0.011) were significantly elevated in patients with refractory ischemic symptoms versus stabilized patients. Temporal monitoring by ELISA of CCL5， CCL18， and soluble CD40 ligand (sCD40) levels revealed a drop in CCL5 and sCD40L levels in all UAP patients from day 2 onward (CCL5 12.1 ng/mL， P<0.001; sCD40L 1.35 ng/mL， P<0.05)， whereas elevated CCL18 levels were sustained for at least 2 days， then were decreased at 180 days after inclusion (34.5 ng/mL， P<0.001). Peripheral blood mononuclear cells showed increased protein expression of chemokine receptors CCR3 and CCR5 in CD3+ and CD14+ cells at baseline compared with 180 days after inclusion， whereas mRNA levels were downregulated， which was attributable in part to a postischemic release of human neutrophil peptide-3-positive neutrophils and in part to negative feedback. Finally， elevated CCL5 and CCL18 levels predicted future cardiovascular adverse events， whereas C-reactive protein and sCD40L levels did not.We are the first to report that CCL18 and CCL5 are transiently raised during episodes of UAP， and peak levels of both chemokines are indicative of refractory symptoms. Because levels of both chemokines， as well as of cognate receptor expression by circulating peripheral blood mononuclear cells， are increased during cardiac ischemia， this may point to an involvement of CCL5/CCL18 in the pathophysiology of UAP and/or post-UAP responses.
Thymic stromal lymphopoietin receptor-mediated IL-6 and CC/CXC chemokines expression in human airway smooth muscle cells: role of MAPKs (ERK1/2, p38, and JNK) and STAT3 pathways.
Thymic stromal lymphopoietin (TSLP) plays a pivotal role in allergic diseases such as asthma， chronic obstructive pulmonary disease， and atopic dermatitis. Enhanced TSLP expression has been detected in asthmatic airways that correlated with both the expression of Th2-attracting chemokines and with disease severity. Although cumulative evidence suggests that human airway smooth muscle (HASM) cells can initiate or perpetuate the airway inflammation by secreting a variety of inflammatory cell products such as cytokines and chemokines， the role of TSLP in this pathway is not known. In the current study， we sought to investigate whether HASM cells express the TSLP receptor (TSLPR) and whether it is functional. We first demonstrated that primary HASM cells express the transcript and protein of both TSLPR subunits (TSLPR and IL-7Ralpha). Functionally， TSLPR-mediated HASM activation induced a significant increase in CXC (IL-8/CXCL8)， CC (eotaxin-1/CCL11) chemokines， and proinflammatory cytokine IL-6 expression. Furthermore， using biochemical and genetic approaches， we found that TSLP-induced proinflammatory gene expression in HASM involved the transcriptional mechanisms， MAPKs (ERK1/2， p38， and JNK)， and STAT3 activation. Finally， TSLPR immunoreactivity in bronchial sections from mild allergic asthmatics suggested the potential in vivo TSLP targeting of HASM. Altogether， our data suggest that the TSLPR-mediated HASM activation induces proinflammatory cytokine and chemokines release that may facilitate inflammatory immune cells recruitment in airways. In addition， it may be inferred that TSLPR is involved in the pathogenesis of allergic asthma through the activation of HASM cells by TSLP.
Blood vessel degeneration is critically involved in nearly all types of degenerative diseases. Therefore strategies to enhance blood vessel protection and survival are highly needed. In this study， using different animal models and cultured cells， we show that PDGF-CC is a potent vascular protective and survival factor. PDGF-CC deficiency by genetic deletion exacerbated blood vessel regression/degeneration in various animal models. Importantly， treatment with PDGF-CC protein not only increased the survival of retinal blood vessels in a model of oxygen-induced blood vessel regression but also markedly rescued retinal and blood vessel degeneration in a disease model of retinitis pigmentosa. Mechanistically， we revealed that heme oxygenase-1 (HMOX1) activity is critically required for the vascular protective/survival effect of PDGF-CC， because blockade of HMOX1 completely abolished the protective effect of PDGF-CC in vitro and in vivo. We further found that both PDGF receptors， PDGFR-β and PDGFR-α， are required for the vasoprotective effect of PDGF-CC. Thus our data show that PDGF-CC plays a pivotal role in maintaining blood vessel survival and may be of therapeutic value in treating various types of degenerative diseases.
Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue.
Macrophage recruitment to adipose tissue in obesity contributes to enhanced adipose tissue inflammatory activity and thus may underlie obesity-associated metabolic dysfunction. Obese adipose tissue exhibits increases in CC chemokine ligand 2 (CCL2， or monocyte chemoattractant protein-1)， an important macrophage-recruiting factor. We therefore hypothesized that elevated CCL2 may contribute to obesity-associated adipose tissue macrophage recruitment. Male 6-week-old CCL2(-/-) and wild-type mice (n = 11-14 per group) were fed standard and high-fat diets until 34 weeks of age. At 12-16 and 25-29 weeks of age， blood was collected for plasma glucose and hormone measurements， and glucose tolerance and insulin tolerance tests were performed. Adipose tissue was collected at 34 weeks for analysis of macrophage infiltration. Surprisingly， CCL2(-/-) mice on high-fat diet showed no reductions in adipose tissue macrophages. CCL2(-/-) mice on standard and high-fat diet were also glucose intolerant and had mildly increased plasma glucose and decreased serum adiponectin levels compared with wild-type mice. On high-fat diet， CCL2(-/-) mice also gained slightly more weight and were hyperinsulinemic compared with wild-type mice. Because macrophage levels were unchanged in CCL2(-/-) mice， the phenotype appears to be caused by lack of CCL2 itself. The fact that metabolic function was altered in CCL2(-/-) mice， despite no changes in adipose tissue macrophage levels， suggests that CCL2 has effects on metabolism that are independent of its macrophage-recruiting capabilities. Importantly， we conclude that CCL2 is not critical for adipose tissue macrophage recruitment. The dominant factor for recruiting macrophages in adipose tissue during obesity therefore remains to be identified.
Abstract Airway inflammation is an important component of cystic fibrosis (CF) lung disease. We sought to determine whether alveolar macrophages were involved in early CF lung disease. Children with CF (median age 3.1 yrs) participated in a surveillance programme that included annual bronchoalveolar lavage (BAL). Control samples were obtained from non-CF children (median age 3.1 yrs; n = 24) investigated for persistent respiratory symptoms. Pulmonary infection was detected in 31% (16 out of 51) and 38% (nine out of 24) of children from the CF and non-CF groups， respectively. Alveolar macrophages in BAL were increased in CF compared with non-CF in the absence of infection (223x10(3) versus 85x10(3) cells.mL(-1); p = 0.001) and were associated with elevations in the CC chemokines (macrophage inflammatory protein (MIP)-3alpha (chemokine (C-C motif) ligand (CCL)20; 355.8 versus 46.0 pg.mL(-1); p<0.001)， monocyte chemotactic protein-1 (CCL2; 263.5 versus 25.3 pg.mL(-1); p<0.001)， MIP-1alpha (CCL3; 38.2 versus 4.9 pg.mL(-1); p<0.001) and MIP-1beta (CCL4; 326.6 versus 27.5 pg.mL(-1); p<0.001)). Total cell counts and neutrophil numbers increased in the presence of infection; however， there was no additional effect of CF. Alveolar macrophages and CC chemokines are elevated in the lungs in young children with CF even in the absence of pulmonary infection. Longitudinal studies are required to determine the clinical relevance of these findings.
IL-17A induces eotaxin-1/CC chemokine ligand 11 expression in human airway smooth muscle cells: role of MAPK (Erk1/2, JNK, and p38) pathways.
Abstract Recently， IL-17A has been shown to be expressed in higher levels in respiratory secretions from asthmatics and correlated with airway hyperresponsiveness. Although these studies raise the possibility that IL-17A may influence allergic disease， the mechanisms remain unknown. In this study， we investigated the molecular mechanisms involved in IL-17A-mediated CC chemokine (eotaxin-1/CCL11) production from human airway smooth muscle (ASM) cells. We found that incubation of human ASM cells with rIL-17A resulted in a significant increase of eotaxin-1/CCL11 release from ASM cells that was reduced by neutralizing anti-IL-17A mAb. Moreover， IL-17A significantly induced eotaxin-1/CCL11 release and mRNA expression， an effect that was abrogated with cycloheximide and actinomycin D treatment. Furthermore， transfection studies using a luciferase-driven reporter construct containing eotaxin-1/CCL11 proximal promoter showed that IL-17A induced eotaxin-1/CCL11 at the transcriptional level. IL-17A also enhanced significantly IL-1beta-mediated eotaxin-1/CCL11 mRNA， protein release， and promoter activity in ASM cells. Primary human ASM cells pretreated with inhibitors of MAPK p38， p42/p44 ERK， JNK， or JAK but not PI3K， showed a significant decrease in eotaxin-1/CCL11 release upon IL-17A treatment. In addition， IL-17A mediated rapid phosphorylation of MAPK (p38， JNK， and p42/44 ERK) and STAT-3 but not STAT-6 or STAT-5 in ASM cells. Taken together， our data provide the first evidence of IL-17A-induced eotaxin-1/CCL11 expression in ASM cells via MAPK (p38， p42/p44 ERK， JNK) signaling pathways. Our results raise the possibility that IL-17A may play a role in allergic asthma by inducing eotaxin-1/CCL11 production.
Naive T cells migrate extensively within lymph node () T zones to scan for Ag-bearing dendritic cells. However， the signals controlling T in are not well defined. In this study， by real-time imaging of ， we show that the inhibition of Gi signaling in T cells severely impairs their migration. The chemokine ， a ligand of ， strongly induces in vitro， and T in from ligand-deficient plt/plt was reduced. -deficient T cells in wild-type showed a similar reduction in motility， and antagonism of function did not further decrease their motility. The effect of or -ligand deficiency could account for approximately 40% of the Gi-dependent motility. These results reveal a role for in promoting T within lymphoid organ T zones， and they suggest the additional involvement of novel Gi-coupled receptors in promoting T at these sites.
CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin.
The chemokine thymus and activation-regulated chemokine (TARC; CCL17) is displayed by cutaneous (but not intestinal) venules， and is thought to trigger vascular arrest of circulating skin homing memory T cells， which uniformly express the TARC receptor CC chemokine receptor (CCR)4. Cutaneous T cell-attracting chemokine (CTACK; CCL27)， expressed by skin keratinocytes， also attracts cutaneous memory T cells， and is hypothesized to assist in lymphocyte recruitment to skin as well. Here we show that chronic cutaneous inflammation induces CD4 T cells expressing E-selectin binding activity (a marker of skin homing memory cells) in draining lymph node， and that these E-selectin ligand+ T cells migrate efficiently to TARC and to CTACK. In 24 h in vivo homing assays， stimulated lymph node T cells from wild-type mice or， surprisingly， from CCR4-deficient donors migrate efficiently to inflamed skin; and an inhibitory anti-CTACK antibody has no effect on wild-type lymphocyte recruitment. However， inhibition with anti-CTACK monoclonal antibody abrogates skin recruitment of CCR4-deficient T cells. We conclude that CTACK and CCR4 can both support homing of T cells to skin， and that either one or the other is required for lymphocyte recruitment in cutaneous delayed type hypersensitivity.