Chemokine Regulated Upon Activation, Normal T Cell Expressed And Secreted Research Articles

RANTES (CCL5) in Patients With Geographic Atrophy Age-Related Macular Degeneration.

A previous study from our research group showed significantly lower levels of RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) in patients with intermediate age-related macular degeneration (AMD) compared to control patients with no AMD. The primary aim of this study was to assess levels of RANTES in a cohort of patients with a more advanced form of the disease, geographic atrophy (GA), in comparison with controls. The study was conducted on a cohort of patients with GA recruited into a Colorado AMD registry. Cases and controls were defined with multimodal imaging. Plasma levels of the chemokine RANTES were measured using a multiplex assay. A nonparametric (rank-based) regression model was fit to RANTES with a sex by AMD category interaction. The plasma levels of RANTES were significantly higher in the control group in comparison to the GA AMD group (median [interquartile range]): 10,204 [5799-19,554] pg/mL vs. 5435 [3420-9177] pg/mL, respectively, P < 0.01). When moderated by sex, there was no statistical difference between the male and female GA AMD or the male and female controls. We found lower level of RANTES in patients with GA AMD compared with controls. This finding is consistent with the findings from our previous intermediate AMD study. However, in contrast to the results of our previous research, when moderated by sex there was no statistical difference between male and female GA patients. The biomarker RANTES is significantly lower in GA AMD patients compared to controls.

Sex Differences in RANTES (CCL5) in Patients With Intermediate Age-Related Macular Degeneration (AMD) and Controls With no AMD.

PurposeTo determine if there are sex differences in levels of regulated upon activation, normal T cell expressed and secreted (RANTES) in patients with intermediate age-related macular degeneration (iAMD) and in controls with no AMD.MethodsPatients with iAMD and controls defined by multi-modal imaging were recruited into a Colorado AMD registry. Plasma levels of the chemokine RANTES were measured using a multiplex assay. A nonparametric (rank-based) regression model was fit to RANTES with a sex by AMD category interaction.ResultsThe plasma level of RANTES was significantly higher in the control group in comparison with the iAMD group. When moderated by sex, RANTES was significantly lower (P = 0.005) in males (median, 4525.6 pg/mL; interquartile range, 2589–7861 pg/mL) compared with females (median, 6686 pg/mL; interquartile range, 3485–12488 pg/mL) within the iAMD cohort. No significant difference was found in levels of RANTES between males and females in the control group.ConclusionsWe found that levels of RANTES were moderated by sex in cases with iAMD with lower levels in males compared with females. The findings illustrate the importance of including sex as a biological variable in AMD research. There is a need for further studies of RANTES, stratified by sex, in the advanced phenotypes of AMD.Translational RelevanceThe biomarker RANTES identified in the plasma of patients with iAMD reflects systemic alterations when stratified by sex.

RANTES/CCL5 Signaling from Jawbone Cavitations to Epistemology of Multiple Sclerosis - Research and Case Studies.

BackgroundThe role played by signaling pathways in the cell–cell communication associated with multiple sclerosis (MS) progression has become a critical area in research. Chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted), also named chemokine C-C motif ligand 5 (CCL5; R/C), is a protein that has been investigated in neuroinflammatory research due to its link to MS development.ObjectiveResearch on bone marrow defects in the jawbone (BMDJ), which morphologically presents as fatty-degenerative osteonecrosis of the jawbone (FDOJ), presents overexpression of R/C signaling in affected areas. Here, we try to elucidate the potential link between jawbone-derived R/C and MS.MethodsSeventeen BMDJ/FDOJ samples extracted from 17 MS patients, as well as samples from 19 healthy controls, were analyzed for R/C expression using bead-based Luminex® analysis. The serum R/C levels from 10 MS patients were examined. Further, bone density, histology, and R/C expression were analyzed in two clinical case studies.ResultsHigh R/C overexpression was found in all BMDJ/FDOJ samples obtained from the MS group. Serum R/C levels were also upregulated in the MS group. R/C serum levels in the MS cohort were higher than in the healthy controls. In contrast, the histology of BMDJ/FDOJ samples showed no inflammatory cells.DiscussionR/C-induced “silent inflammation” in MS is widely discussed in the scientific literature, along with R/C triggering of inflammation in the central nervous system, which might be key in the development of MS.ConclusionThe authors suspect that BMDJ/FDOJ may serve as a trigger of MS progression via R/C overexpression. As such, the dental and medical communities should be made aware of BMDJ/FDOJ in cases of MS.

Jawbone Cavitation Expressed RANTES/CCL5: Case Studies Linking Silent Inflammation in the Jawbone with Epistemology of Breast Cancer.

BackgroundThe role of signaling pathways as part of the cell-cell communication within cancer progression becomes a crucial area. Chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted), also known as the chemokine C-C motif ligand 5 (CCL5) (R/C), is a protein on which cancer research focus due to its link with aggressive cancer development.ObjectiveResearch on fatty-degenerative osteonecrosis in jawbone (FDOJ) shows striking overexpression of R/C in these areas. Here we try to elucidate a potential link between jawbone-derived R/C and breast cancer (BC) and compare these findings by immunohistochemical staining.MethodsThirty-nine FDOJ samples extracted from 39 BC patients and samples from 19 healthy control were analyzed for R/C expression using bead-based Luminex® analysis. R/C levels from 5 BC patients were measured in serum before and after FDOJ surgery. Bone density, histology, R/C expression, and immunohistochemistry were analysed in 4 clinical case studies. The R/C staining of two FDOJ BC patients is compared with the immunohistochemical staining of BC cell preparations.ResultsA high overexpression of R/C was seen in all FDOJ samples. R/C levels in serum were statistically downregulated after FDOJ surgery (p=0.0241).DiscussionR/C induced “silent inflammation” in BC is widely discussed in scientific papers along with R/C triggering of different signaling pathways, which might be a key point in the development of BC.ConclusionHypothesis that FDOJ may serve as a trigger of BC progression through R/C overexpression was set by the authors, who thus inspire clinicians to make aware of FDOJ throughout the dental and medical community in BC cases.

The Involvement of the Chemokine RANTES in Regulating Luminal Acidification in Rat Epididymis.

BackgroundA complex interplay between different cell types in the epithelium leads to activation of the luminal acidifying capacity of the epididymis, a process that is crucial for sperm maturation and storage. Basal cells sense the luminal angiotensin II (ANG II) and stimulate proton secretion in clear cells through nitric oxide (NO). Our previous study has shown the chemokine regulated upon activation normal T-cell expressed and secreted (RANTES) was expressed in the F4/80 positive macrophages of human epididymis. The objective of this study was to explore the involvement of RANTES in regulating the luminal acidification in the rat epididymis.MethodsThe role of RANTES was investigated by in vivo perfusion with recombinant RANTES, Met-RANTES, and PBS of different pH values. Furthermore, rats vasectomy was performed to alter the epididymal luminal pH. RIA was used to measure the tissue homogenate ANG II concentration. Real time-PCR and western blot were employed to examine the expression levels of AGTR2, RANTES, CCR1, CCR5, and iNOS in epididymis.ResultsRANTES was restricted to the basal macrophages of epididymal ducts and co-localized with its receptors CCR1 and CCR5. Both V-ATPase and iNOS were up-regulated in the cauda epididymis after perfused with recombinant RANTES, while the antagonist Met-RANTES perfusion led to a complete abrogation of the increased expression of V-ATPase in the apical membrane of clear cells and iNOS in macrophages. Upon alkaline perfusion, RANTES expression was significantly increased and the apical accumulation of V-ATPase in the clear cells was induced in the cauda epididymis. The luminal pH in the cauda epididymis increased after vasectomy. The concentration of the ANG II and the expression levels of AGTR2, RANTES, CCR1, CCR5, and iNOS dropped in the cauda epididymis following vasectomy.ConclusionUpon the activation of basal cells, RANTES might induce the NO release from macrophages by interacting with its receptors, which increases proton secretion by adjacent clear cells. Thus, RANTES is possible to participate in the crosstalk among basal cells, macrophages and clear cells for the fine control of an optimum acidic luminal environment that is critical for male fertility.

Increased chemokine RANTES in synovial fluid and its role in early-stage degenerative temporomandibular joint disease.

Degenerative joint disease (DJD) of the temporomandibular joints (TMJs) in adolescents and young adults is closely associated with disc displacement without reduction (DDw/oR). This study aimed to determine the pathogenesis of early-stage TMJ DJD induced by DDw/oR. 31 female subjects aged 12-30years were enrolled, comprising 12 patients with DDw/oR without DJD, 13 with DDw/oR and early-stage DJD, and 6 healthy volunteers. The synovial fluid samples of the subjects were screened for 27 inflammatory-related cytokines using multiple cytokine array. Significantly increased cytokines and a key regulator of osteoclastogenesis "receptor activator of nuclear factor-κB ligand" (RANKL) were further determined by sandwich immunoassay. These factors were also assessed for the possible pathophysiologic actions on RAW264.7 cell proliferation, migration, osteoclastogenesis and bone-resorbing activity using Cell Counting Kit-8, Transwell system, tartrate-resistant acid phosphatase staining and osteo assay plates. Macrophage-derived inflammatory protein-1 beta (MIP-1β) and regulated upon activation normal T cell expressed and secreted (RANTES) were found to vary significantly in relation to the controls. In contrast to an unchanged concentration of RANKL, a strong increase in the level of RANTES was detected in subjects with DDw/oR and early-stage DJD. MIP-1β concentrations were only elevated in subjects with DDw/oR without DJD. Functionally, both MIP-1β and RANTES could enhance macrophage migration in a concentration-dependent manner, while only RANTES exhibited a promoting effect on osteoclast formation and bone-resorbing activity. Chemokine RANTES was significantly upregulated and might be a key regulator of osteoclastogenesis contributing to DDw/oR-induced early-stage TMJ DJD.

HHV-6 Infection and Chemokine RANTES Signaling Pathway Disturbance in Patients with Autoimmune Thyroiditis.

The aim of this study was to investigate the role of human herpesvirus-6 (HHV-6) in autoimmune thyroiditis (AIT) development. We examined the possible involvement of HHV-6 gene expression encoding immunomodulating proteins U12 and U51 in AIT development and their role in the modulation of chemokine signaling. One hundred patients with autoimmune thyroiditis following thyroidectomy were enrolled in this study. Nested polymerase chain reaction (nPCR) was used to detect the HHV-6 sequence in DNA samples. Reverse transcription PCR (RT-PCR) with three different HHV-6 gene targets (U79/80, U51 and U12) was to detect active infection markers. HHV-6 load was identified using a commercial real-time PCR kit. Immunohistochemistry was performed to investigate the expression of the HHV-6 antigen and RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) in thyroid gland tissue. Different commercial immunosorbent assay kits were used for the detection of RANTES, IFNγ, IL-6, and TNFα levels in the AIT patient group and controls. We detected 98% presence of the HHV-6 genomic sequence in AIT patients’ thyroid gland tissues. Markers of active HHV-6 infection (HHV-6 U79/80, U12 and/or U51 mRNA) were predominant in AIT patients’ thyroid tissue samples in comparison with the control group (56% vs. 6%). Evidence from immunofluorescence microscopy showed that HHV-6 can persist in thyrocytes and can interact with RANTES. Visual confirmation of the intense immunofluorescence signal of RANTES detected in thyroid tissues could indicate high expression of this chemokine in the thyroid gland. On the other hand, immunosorbent assays showed very low RANTES levels in AIT patients’ peripheral plasma. These results indicate that RANTES level in AIT patients could be influenced by HHV-6 activation, which in turn may aid AIT development.

Osteoarthritis-related biomarkers profile in chronic anterior cruciate ligament injured knee

ObjectiveIncreasing evidence has shown the involvement of the innate immune system and inflammatory response in osteoarthritis (OA) pathogenesis; however, anterior cruciate ligament (ACL) tears are recognized risk factors for development of post-traumatic OA. We investigated (1) whether inflammatory mediators involved in OA pathogenesis are also present at significant concentrations in the knee joint sometime after ACL complete tear and may be considered as prognostic biomarkers of progression to secondary OA; and (2) whether quantification in serum may surrogate synovial fluid (SF) measurements in both cases. MethodsThirty-seven end-stage OA patients and 33 patients with ACL complete tear that were included on the waiting list for knee surgery were consecutively recruited. Serum and SF samples were taken before surgery, and tumor necrosis factor-alpha, (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-1 (MMP1), matrix metalloproteinase-3 (MMP3), tissue inhibitor of metalloproteinase-1 (TIMP1), bone morphogenetic protein-7 (BMP7), regulated upon activation normal t-cell expressed and secreted (RANTES), cytokine interferon-γ-induced protein 10 (IP-10) and heat shock protein family A (Hsp70) member 1A (HSPA1A) were quantified by enzyme-linked immunosorbent assay (ELISA.) Normally distributed data were compared using a one-way analysis of variance (ANOVA) test. Data not normally distributed were analyzed using a nonparametric Mann–Whitney rank sum test. Differences in means were compared using a Student's t-test. Correlations were analyzed using Pearson's coefficient of variation. ResultsEighty-seven percent of patients with OA and 86% of those with ACL tear had quantifiable levels of biomarkers in SF. SF levels of IL-6, IL-8, MMP1, MMP3, RANTES, IP-10, BMP7 and HSPA1A were significantly lower in ACL injury knees compared with those with OA, but much higher than those reported in control subjects. Serum levels of IL-6, IP-10, and MMP1 were also lower in patients with ACL tears, who had, however, significantly higher TNF-α, HSPA1A, and TIMP1 levels when compared with OA patients. Levels of biomarkers tested in serum and SF samples were significantly different. ConclusionsOur data propose that cytokines IL-6 and IL-8 and the chemokines RANTES, IP-10, MMP1, MMP3, and HSPA1A may be involved in the inflammatory process leading to synovitis, the central lesion in OA onset and development; persistent high levels of these substances sometime after ACL injury suggest that they could play an etiopathogenic role in the maintenance of the inflammatory environment leading to post-traumatic OA. Serum biomarker levels do not appear to faithfully reflect what occurs inside the joint. Thus, most biomarkers cannot yet be considered as useful inflammatory biomarkers of knee joint diseases.

Cancer immunotherapy using the Fusion gene of Sendai virus.

Inactivated Sendai virus particle (or hemagglutinating virus of Japan envelope; HVJ-E) has been previously reported to possess antitumour properties that activate antitumour immunity. Two glycoproteins, fusion (F) and hemagglutinin-neuraminidase (HN), are present on the surface of HVJ-E. HN is necessary for binding to receptors such as acidic gangliosides, and F induces membrane fusion by associating with membrane lipids. We previously reported that liposomes reconstituted with F but not HN showed antitumour activity by inducing IL-6 secretion in dendritic cells (DCs), suggesting that F protein is capable of eliciting antitumour activity. Here, we attempted to deliver F gene into tumour tissue in mice by electroporation and demonstrated that F gene therapy retarded tumour growth, increased CD4+ and CD8+ T-cell infiltration into tumours and induced tumour-specific IFN-γ T-cell response. However, neutralisation of IL-6R signalling did not impact F plasmid-mediated antitumour effect. Instead, we found that F plasmid treatment resulted in a significant increase in the secretion of the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted) by tumour-infiltrating T cells. Neutralising antibody against RANTES abolished the antitumour effect of F plasmid treatment in a dose-dependent manner. Thus, F gene therapy may show promise as a novel therapeutic for single or combined cancer immunotherapy.

Leukocyte chemotactic cytokine and leukocyte subset responses during ultra-marathon running

PurposeThe aim of this study was to assess leukocyte chemotactic cytokine and leukocyte subset responses during ultra-marathon running. Leukocyte chemokines such as interleukin (IL)-8, interferon gamma-induced protein-10 (IP-10), regulated upon activation, normal T-cell expressed and secreted (RANTES), and eotaxin are involved in leukocyte recruitment. MethodsAmong 60 male amateur endurance runner volunteers, 18 finished the course (a 308km continuous race from Kanghwado to Kangneung, South Korea). Their average age, height, and body mass were 52.8±5.0years, 167.6±5.2cm, and 64.5±1.2kg, respectively. Blood samples were collected at 0, 100, 200, and 308km during the race for analysis of white blood cells and serum concentrations of IL-8, IP-10, RANTES, eotaxin, IL-6, creatine kinase (CK), and C-reactive protein (CRP). ResultsMuscle and liver damage indicators (IL-6, CK, and CRP) were maximally elevated as a result of marathon running. Total leukocytes, neutrophils, and monocytes increased significantly during the event (leukocytosis, neutrophilia, and monocytosis, respectively). However, lymphocytes and eosinophils decreased significantly during the event (lymphopenia and eosinopenia, respectively). Serum levels of the neutrophil chemokine IL-8 increased maximally at 100km and were maintained. Monocyte-lymphocyte chemokine IP-10 concentration decreased during the latter part of the race. The eosinophil chemokine eotaxin decreased gradually during the race, and no difference was observed in eosinophil chemokine RANTES levels. ConclusionThese observations indicate that prolonged endurance ultra-marathon running was associated with significant systemic inflammation and perturbation in leukocyte subsets. Leukocyte chemotactic cytokines such as IL-8, IP-10, eotaxin showed similar patterns of responses in related leukocyte subsets, but RANTES did not.

Correlations between chemokines CXCL12, CCL2, RANTES and early abortion

To explore the correlations between chemokines stromal cell-derived factor-1 (CXCL12), monocyte chemotactic protein-1 (CCL2), regulated upon activation normal T cell expressed and secreted (RANTES) and early abortion. The villus and decidua tissues of recurrent spontaneous abortion group (n = 26), medical abortion group (n = 30) and normal early pregnancy women (control group, n = 30) were collected at our hospital from 2008 to 2009. And their expressions of CXCL12, CCL2, RANTES mRNA were determined by real-time fluorescence quantitative PCR (polymerase chain reaction). The CXCL12, CCL2 and RANTES mRNA gene expressions were detected in first-trimester placental villus and decidua tissues. And the gene expressions of CXCL12 mRNA in villus and decidua tissues in spontaneous abortion and medical abortion groups were significantly lower than that in the control group (P < 0.01). But the gene expressions of CCL2 and RANTES mRNA in villus and decidua tissues were significantly higher than that in the control group (P < 0.01). CXCL12, CCL2 and RANTES are co-expressed in human villus and decidua tissues. The lower CXCL12 mRNA expression and the higher expressions of CCL2 and RANTES mRNA play important roles in the pathogenesis of early abortion.

Serum Chemokines RANTES and Monocyte Chemoattractant Protein-1 in Egyptian Patients with Atopic Asthma: Relationship to Disease Severity

Asthma is a highly prevalent, complex inflammatory disease of the airways often associated with bronchial hyperreactivity and atopy. The chemokine RANTES (regulated upon activation, normal T -cell expressed and secreted) is an important element for the chemotaxis at the site of allergic inflammation. This study aimed to assess the serum levels of the chemokines RANTES and monocyte chemoattractant protein-1 (MCP-1) in Egyptian patients with atopic asthma and to evaluate their possible relation t the severity of airway obstruction. The study included 60 Egyptian patients with atopic asthma and 20 healthy volunteers. Serum levels of the chemokines RANTES and MCP-1 were measured. Total serum IgE level and absolute eosinophil counts were determined. The severity of airway obstruction was assessed using spirometric measurement (FEV(1)). The serum levels of RANTES were significantly higher in all asthmatic patients than the controls (p <0.001). Moreover, RANTES levels were significantly increased in patients with moderate and severe asthma as compared to those with mild asthma (p <0.001). Serum RANTES correlated positively with absolute eosinophil counts and total serum IgE and negatively with FEV(1), whereas there was no significant correlation with serum MCP-1 in all asthmatic patients. Serum RANTES may be used as a useful noninvasive marker of airway obstruction and a potential diagnostic tool for monitoring asthma severity. In this regard, identification and blocking of this chemokine and/or its receptor may be a promising therapeutic approach to asthmatic patients.

Angiogenic properties of the chemokine RANTES/CCL5

Atherosclerosis is an inflammatory disease that is one of the leading causes of death in developed countries. This disease is defined by the formation of an atherosclerotic plaque, which is responsible for artery obstruction and affects the heart by causing myocardial infarction. The vascular wall is composed of three cell types and includes a monolayer of endothelial cells and is irrigated by a vasa vasorum. The formation of the vascular network from the vasa vasorum is a process involved in the destabilization of this plaque. Cellular and molecular approaches are studied by in vitro assay of activated endothelial cells and in in vivo models of neovascularization. Chemokines are a large family of small secreted proteins that have been shown to play a critical role in the regulation of angiogenesis during several pathophysiological processes such as ischaemia. Chemokines may exert their regulatory activity on angiogenesis directly by activating the vasa vasorum, or as a consequence of leucocyte infiltration through the endothelium, and/or by the induction of growth factor expression such as that of VEGF (vascular endothelial growth factor). The present review focuses on the angiogenic activity of the chemokines RANTES (regulated upon activation, normal T-cell expressed and secreted)/CCL5 (CC chemokine ligand 5). RANTES/CCL5 is released by many cell types such as platelets or smooth muscle cells. This chemokine interacts with GPCRs (G-protein-coupled receptors) and GAG (glycosaminoglycan) chains bound to HSPGs (heparan sulfate proteoglycans). Many studies have demonstrated, using RANTES/CCL5 mutated on their GAG or GPCR-binding sites, the involvement of these chemokines in angiogenic process. In the present review, we discuss two controversial roles of RANTES/CCL5 in the angiogenic process.

Cytokine and Chemokine Responses to Selected Early Secreted Antigenic Target-6 and Culture Filtrate Protein-10 Peptides in Tuberculosis

Cytokine [tumor necrosis factor-α, interleukin-2 (IL-2), IL-4] and chemokine [regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein-1] responses to selected early secreted antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) peptides were studied in healthy household contacts and patients with pulmonary tuberculosis (PTB). It was observed that Th1 cytokines and chemokine RANTES positive T cells were elevated in response to the peptides Esp1, Esp6, Cfp6, and Cfp8 in healthy household contacts. IL-4 positive T cells were enhanced by Esp1 and Esp6 in PTB. Monocyte chemoattractant protein-1 positive monocytes increased in response to the peptides Esp1, Esp6, Cfp8, and Cfp9 in PTB. These peptides deserve attention for further immune studies.

Modulation of the bovine innate immune response by production of 1α,25-dihydroxyvitamin D3 in bovine monocytes

In cattle, the kidney has been the only known site for production of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] from 25-hydroxyvitamin D3 [25(OH)D3] by 1α-hydroxylase (1α-OHase). Based on human studies, it was hypothesized that bovine monocytes could produce 1,25(OH)2D3 upon activation and 1,25(OH)2D3 would regulate expression of vitamin D–responsive genes in monocytes. First, the effects of 1,25(OH)2D3 on bovine monocytes isolated from peripheral blood were tested. Treatment of nonstimulated monocytes with 1,25(OH)2D3 increased expression of the gene for the vitamin D 24-hydroxylase (24-OHase) enzyme by 51±13 fold, but 1,25(OH)2D3 induction of 24-OHase expression was blocked by lipopolysaccharide (LPS) stimulation. In addition, 1,25(OH)2D3 increased the gene expression of inducible nitric oxide synthase and the chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted) in LPS-stimulated monocytes 69±13 and 40±12 fold, respectively. Next, the ability of bovine monocytes to express 1α-OHase and produce 1,25(OH)2D3 was tested. Activation of monocytes with LPS, tripalmitoylated lipopeptide (Pam3CSK4), or peptidoglycan caused 43±9, 17±3, and 19±3 fold increases in 1α-OHase gene expression, respectively. Addition of 25(OH)D3 to LPS-stimulated monocytes enhanced expression of inducible nitric oxide synthase and RANTES and nitric oxide production in a dose-dependent manner, giving evidence that activated monocytes convert 25(OH)D3 to 1,25(OH)2D3. In conclusion, bovine monocytes produce 1,25(OH)2D3 in response to toll-like receptor signaling, and 1,25(OH)2D3 production in monocytes increased the expression of genes involved in the innate immune system. Vitamin D status of cattle might be important for optimal innate immune function because 1,25(OH)2D3 production in activated monocytes and subsequent upregulation of inducible nitric oxide synthase and RANTES expression was dependent on 25(OH)D3 availability.

Effects of RANTES and MBL2 gene polymorphisms in sickle cell disease clinical outcomes: Association of the g.In1.1T&gt;C RANTES variant with protection against infections

Sickle cell anemia (SCA) is a single-gene mutation genetic disease characterized by a highly variable clinical presentation. Genetic modifiers of the general outcome have been reported, some of them linked to the α-and β-globin gene clusters. In addition, polymorphisms linked to various genes have been associated with specific complications of the disease. We studied the polymorphisms of two candidate genes, MBL2 (Mannose-Binding Lectin 2) and chemokine RANTES (Regulated upon Activation, normal T cell-Expressed and Secreted), in relation to infectious complications in a series of 115 patients with SCA living in two different environments: Benin and France. All the patients were identified at birth and followed for 5 years. All were homozygotes for the βS Benin hapio- type. Our results show no association of MBL2 variants with infectious events, but we observed for the first time that patients carrying the g.ln1.1C RANTES variant had a lower risk of recurrence of bacterial infections, suggesting a protective effect conferred by the variant.

Expression and Secretion of RANTES (CCL5) in Human Adipocytes in Response to Immunological Stimuli and Hypoxia

Obesity and related disorders represent states of systemic low-grade inflammation. Chemokine secretion by adipocytes may initiate leukocyte infiltration in obese adipose tissue and thus mediate an important step in the establishment of chronic immune activation. The chemokine RANTES (regulated upon activation normal T cell expressed and secreted)/CCL5 is a chemoattractant for various leukocyte subsets. This study was designed to examine whether RANTES is expressed and released by human adipocytes and how its expression is regulated. RANTES expression under basal conditions was studied in mature adipocytes. Cells were therefore challenged with lipopolysaccharide (LPS), interferon (IFN)-gamma, interleukin (IL)-4, monocyte chemoattractant protein (MCP)-1 or exposed to low oxygen pressure. RANTES was expressed and secreted constitutively in most samples of mature adipocytes from the omental and the subcutaneous depot. RANTES release was dependent on adipocyte size and also seemed to be higher from cells of obese donors. Hypoxia (4% O (2)) caused an approximately 36% increase of RANTES release. Human adipocytes express the chemokine RANTES and are thus identified as a novel cellular source of this immune mediator. LPS and IFNgamma do not seem to play a significant role for the expression of RANTES in contrast to moderate hypoxia, which points to a distinct role in the innate immune system.

Plasma Levels of the Beta Chemokine Regulated Upon Activation, Normal T Cell Expressed, and Secreted (RANTES) Correlate With Severe Brain Injury

The expression of the beta chemokine RANTES (regulated upon activation, normal T cell expressed, and secreted) has previously been shown to be elevated after traumatic brain injury (TBI) in animal models, but it was unknown whether the plasma level of RANTES was predictive of TBI in critically injured trauma patients. A prospective study was conducted on 108 critically ill trauma patients. Patients were stratified by radiologic diagnosis of TBI. Severe TBI was classified as the presence of diffuse axonal injury, midline shift, or herniation based on admission head computed tomography findings. Serum levels were evaluated at admission and hospital day 7. RANTES was measured using Luminex multiplex assays. Fifty-four patients with and without TBI were compared. Severe TBI was diagnosed in 23 of the 54 TBI patients (43%) and mild/moderate TBI was found in 31 (57%) patients. The mean age of the study population was 43 +/- 20 years with a mean Injury Severity Score of 29 +/- 14. There was no significant difference between groups in age, sex, and Injury Severity Score. At admission, RANTES was significantly higher in patients with severe brain injury than in non-TBI patients (mean 1,339 pg/mL vs. 708 pg/mL, p = 0.046), and there was a trend toward significance when comparing patients with severe versus mild/moderate brain injury (mean 1,339 pg/mL vs. 752 pg/mL, p = 0.069). There was no statistically significant difference on day 7. RANTES was a significant early marker of severe TBI in critically injured trauma patients, consistent with animal models. Future research on the role of RANTES in the pathogenesis of human TBI is warranted.

Chemokine RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) in Multiple Myeloma and MGUS (Monoclonal Gammopathy of Undetermined Significance).

Introduction: Bone disease in patients with myeloma is the devastating complication. RANTES (CCR chemokine, Regulated upon Activation,Normal T Cell Expressed and Secreted) is involved in the bone remodeling that is made by coupled functions of osteoclasts and osteoblasts. Osteoclasts represent the RANTES receptor CCR1 and product RANTES. Osteoblasts express CCR1,3,4,5, and also product RANTES. Osteoblasts chemotaxicaly move to osteoclasts to repair the absorbed bone lesions (Shozo Yano et al., Endocrinology Vol.145, No.5, 2324–2335). The bone pathophysiology of multiple myeloma is the distortion of the well-balanced functions of osteoclast and osteobast. The change of RANTES may be representative of this distortion and the restoration of bone.Method: Blood samples were collected from 54 patients with Multiple Myeloma, 15 patients with MGUS, 41 from donors (30 healthy people or 11 people who have no bone disease). Plasma samples were separated and analyzed by ELISA to determine the levels of RANTES.Result: In healthy people, RANTES changes in proportion to ages with sexual difference. The value of RANTES is 155000pg/ml in20ys male, 51100pg/ml in 20ys female, 133000pg/ml in 40ys male and 78933 pg/ml in 40ys female. The difference of male and female becomes smaller and the value becomes nearly 60000pg/ml at sixty ages in male and female. Serum-bone specific alkaline phosphatase (BAP) is a biochemical indicator of bone turnover and urinary collagen type 1 cross-linked N-telopeptide (NTX) excretion normalized to creatinine (NTX/Cr) from urine sample is a bone resorption marker. At sixty ages, BAP and NTX/Cr become lower in accord with RANTES. In Myeloma cases, RANTES is about 20000pg/ml lower than the age-related value in female and about 75000pg/ml higher in male. After the treatment, RANRES increases in most of patients (both male and female) who have got response after chemotherapy. The rise of female is average 34566pg/ml but the rise of male is very small, average 5250pg/ml, because RANTES has already increased before chemotherapy. Beyond our expectation,RANTES of MGUS is almost the same as Myeloma.Discussion: The bone remodeling activity of male is higher than female and may be easily induced by the chance of bone absorption. The data suggest that tumor growth suppression produces the recovery of the remodeling. The value of RANTES of MGUS indicates why some patients with MGUS have the punched-out lesions like Myeloma.Conclusion: This study has turned out for the first time that RANTES is associated with the bone pathophysiology of multiple myeloma and MGUS.

Met-RANTES reduces endothelial progenitor cell homing to activated (glomerular) endothelium in vitro and in vivo

The chemokine RANTES (regulated upon activation normal T-cell expressed and secreted) is involved in the formation of an inflammatory infiltrate during glomerulonephritis. However, RANTES receptor inhibition, although reducing glomerular leukocyte infiltration, can also increase damage. We hypothesized that RANTES does not only promote the influx and activation of inflammatory leukocytes but also mediates glomerular microvascular repair by stimulating the homing of bone marrow (BM)-derived endothelial progenitor cells. To investigate the role of RANTES in the participation of BM-derived cells in glomerular vascular repair, we used a rat BM transplantation model in combination with reversible anti-Thy-1.1 glomerulonephritis. Twenty-four hours after the induction of glomerulonephritis, BM-transplanted rats were treated for 7 days with either the RANTES receptor antagonist Met-RANTES or saline. The participation of BM-derived endothelial cells in glomerular repair, glomerular monocyte infiltration, and proteinuria was evaluated at days 7 and 28. Furthermore, we used an in vitro perfusion chamber assay to study the role of RANTES receptors in shear-resistant adhesion of the CD34+ stem cells to activated endothelium under flow. In our reversible glomerulonephritis model, RANTES receptor inhibition specifically reduced the participation of BM-derived cells in glomerular vascular repair by more than 40% at day 7 without impairing monocyte influx. However, no obvious change in recovery from proteinuria or morphological damage was observed. Blockade of RANTES receptors on CD34+ cells in vitro partially inhibited platelet-enhanced, shear-resistant firm adhesion of the CD34+ cells to activated endothelium. In conclusion, our data suggest that RANTES is involved in the homing and participation of BM-derived endothelial cells in glomerular repair.