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At least 19 recordsLinked to original sources
PubMed2000

TNF-alpha-induced secretion of C-C chemokines modulates C-C chemokine receptor 5 expression on peripheral blood lymphocytes.

Peripheral blood lymphocytes express CCR5, a chemokine receptor for immune cell migration and calcium signaling that serves as an important coreceptor for the HIV. After in vitro stimulation, CCR5 expression is dramatically increased on mature T lymphocytes, especially on the CD45RO+ memory subset. In this study, we report that TNF-alpha delays the surface expression of CCR5 on PBLs after activation and diminishes CCR5 irrespective of its initial level. Functional loss of CCR5 is reflected in a decreased capability of the treated cells to migrate and signal calcium after MIP-1beta stimulation. The effect is mediated via the p80 type II TNF receptor (TNFR2), which induces NF-kappaB among other factors, leading to an enhanced secretion of the chemokines macrophage-inflammatory protein-1alpha, macrophage-inflammatory protein-1beta, and RANTES. Expression of these chemokines directly down-regulates CCR5. These findings reveal a new regulatory mechanism utilized by activated peripheral T cells to modulate their chemotaxis and potentially other functions mediated by CCR5, including the infection of T lymphocytes by macrophage-tropic HIV strains.

Antibodies↗
PubMed2005

Epigenetic up-regulation of C-C chemokine receptor 7 and C-X-C chemokine receptor 4 expression in melanoma cells.

Histone deacetylation and DNA methylation establish epigenetic modifications, which through chromatin remodeling may result in gene silencing. We hypothesized that chemokine receptors C-C chemokine receptor 7 (CCR7) and C-X-C chemokine receptor 4 (CXCR4) on melanoma cells undergo epigenetic regulation. We investigated whether a histone deacetylase inhibitor and a demethylating agent influence CCR7 and CXCR4 expression on melanoma cells. Initially, microarray analysis was done to screen changes in chemokine receptor expression on melanoma cells after treatment with trichostatin A (TSA) and 5-Aza-2-deoxycytidine (5-Aza). CCR7 and CXCR4 mRNA expression were uniformly altered and selected for further investigation. Quantitative real-time reverse transcription-PCR assay, immunohistochemistry, and Western blot analysis were used to assess changes in mRNA and protein expression induced by TSA and 5-Aza in melanoma lines. Cell migration assays were conducted to assess the effects of altered CCR7 and CXCR4 expression on cell function. Treatment with TSA or 5-Aza increased gene expression of both CCR7 and CXCR4 in melanoma lines. TSA was the strongest enhancer. With combined treatment, CCR7 and CXCR4 mRNA expression was also up-regulated. Immunohistochemistry after combined treatment showed enhanced staining of both CCR7 and CXCR4 compared with control cells. Melanoma cell migration in TSA- and 5-Aza-treated cells was 7- and 2-fold higher than control cells for CCR7 and CXCR4, respectively. In summary, a histone deacetylase inhibitor and a demethylating agent up-regulated CCR7 and CXCR4 expression on melanoma cells. This increase in chemokine receptor expression correlated with functional activity. Most importantly, we have identified an epigenetic mechanism that may endogenously regulate chemokine receptor expression on melanoma cells.

Acetylation↗
PubMed1995

C-C chemokines, but not the C-X-C chemokines interleukin-8 and interferon-gamma inducible protein-10, stimulate transendothelial chemotaxis of T lymphocytes.

Eight chemokines were tested for ability to elicit transendothelial chemotaxis of unstimulated peripheral blood T lymphocytes. The C-C chemokines monocyte chemotactic protein (MCP)-2, MCP-3, RANTES, macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and, as previously described, MCP-1 induced significant, dose-dependent transendothelial chemotaxis of CD3+ T lymphocytes. In contrast, the C-X-C chemokines interleukin-8 (IL-8) and interferon-gamma inducible protein-10 (IP-10) failed to induce transendothelial chemotaxis of CD3+ T lymphocytes or T lymphocyte subsets. RANTES, MIP-1 alpha, and MIP-1 beta induced significant transendothelial chemotaxis of CD4+, CD8+, and CD45R0+ T lymphocyte subsets. Phenotyping of mononuclear cells that underwent transendothelial migration to MCP-2, MCP-3, RANTES, or MIP-1 alpha showed both monocytes and activated (CD26 high), memory-type (CD45R0+) T cells. Both CD4+ and CD8+ T lymphocytes were recruited, but not natural killer cells or significant numbers of B cells. MCP-2 was the only C-C chemokine tested that attracted a significant number of naive-type (CD45RA+) T lymphocytes. In the absence of endothelium, IL-8 but not IP-10 promoted modest but significant chemotoxis of CD3+ T lymphocytes. Our data support the hypothesis that C-C, not the C-X-C chemokines IL-8 or IP-10, promote transendothelial chemotaxis of T lymphocytes.

CD3 Complex↗
PubMed1998

Identification of C-C chemokine receptor 1 (CCR1) as the monocyte hemofiltrate C-C chemokine (HCC)-1 receptor.

Hemofiltrate C-C chemokine (HCC)-1 is a recently cloned C-C chemokine that is structurally similar to macrophage inflammatory protein (MIP)-1alpha. Unlike most chemokines, it is constitutively secreted by tissues and is present at high concentrations in normal human plasma. Also atypical for chemokines, HCC-1 is reported not to be chemotactic for leukocytes. In this paper, we have investigated the chemokine receptor usage and downstream signaling pathways of HCC-1. Cross-desensitization experiments using THP-1 cells suggested that HCC-1 and MIP-1alpha activated the same receptor. Experiments using a panel of cloned chemokine receptors revealed that HCC-1 specifically activated C-C chemokine receptor (CCR)1, but not closely related receptors, including CCR5. HCC-1 competed with MIP-1alpha for binding to CCR1-transfected cells, but with a markedly reduced affinity (IC50 = 93 nM versus 1.3 nM for MIP-1alpha). Similarly, HCC-1 was less potent than MIP-1alpha in inducing inhibition of adenylyl cyclase in CCR1-transfected cells. HCC-1 induced chemotaxis of freshly isolated human monocytes, THP-1 cells, and CCR1-transfected cells, and the optimal concentration for cell migration (100 nM) was approximately 100-fold lower than that of MIP-1alpha (1 nM). These data demonstrate that HCC-1 is a chemoattractant and identify CCR1 as a functional HCC-1 receptor on human monocytes.

Cell Line↗
PubMed2002

C-C chemokine receptor 2 and C-C chemokine receptor 5 genotypes in patients treated for chronic hepatitis C virus infection.

We explored the influence of the major CCR5 promoter or coding region variants as haplotypes and genotypes in a cohort of 250 chronically infected HCV patients receiving combined interferon/ ribavirin therapy. No haplotype, including the D32-bearing haplotype (G*2) reportedly associated in homozygotes with high HCV viral load (VL), showed a similar effect. Patients with genotype C/G*2 showed slightly lower median VL (p = 0.05). Neither the G*2 haplotype nor the C/G*2 genotype influenced viral dynamics during the initial 12 wk of treatment (p = 0.53). The genotype E/E was more frequent among sustained responders (15.5%) than non-responders (7.8%), and VL declined further among E/E homozygotes during the initial 12 wk of treatment, particularly those with HCV genotype 1 (p = 0.016). Differential receptor expression due to E/E homozygosity in HCV infection remains to be confirmed.

Adult↗
PubMed2004

Induction of C chemokine XCL1 (lymphotactin/single C motif-1 alpha/activation-induced, T cell-derived and chemokine-related cytokine) expression by HIV-1 Tat protein.

HIV-1 Tat has been proposed as a key agent in many AIDS-related disorders, including HIV-1-associated neurological diseases. We have recently shown that Tat expression induces a significant increase in T lymphocytes in the brains of Tat transgenic mice. The CNS infiltration of T lymphocytes has been noted in AIDS patients. In the present study using this unique genetic system we attempted to understand the underlying mechanisms of Tat expression-induced infiltration of T lymphocytes by examining chemokine expression. RNase protection assay revealed that in addition to CCL2 (monocyte chemoattractant protein-1), CCL3 (macrophage inflammatory protein-1alpha (MIP-1alpha)), CCL4 (MIP-1beta), CCL5 (RANTES), CXCL2 (MIP-2), and CXCL10 (inducing protein-10), XCL1 (lymphotactin/single C motif-1alpha/activation-induced, T cell-derived and chemokine-related cytokine) was identified to be up-regulated by Tat expression. XCL1 is a C chemokine and plays a specific and important role in tissue-specific recruitment of T lymphocytes. Thus, we further determined the relationship between Tat and XCL1 expression. Tat-induced XCL1 expression was further confirmed by XCL1-specific RT-PCR and ELISA. Combined in situ hybridization and immunohistochemical staining identified astrocytes, monocytes, and macrophages/microglia as XCL1-producing cells in vivo. Using human astrocytes, U87.MG cells, as an in vitro model, activation of XCL1 expression was positively correlated with Tat expression. Moreover, the XCL1 promoter-driven reporter gene assay showed that Tat-induced XCL1 expression occurred at the transcriptional level. Taken together, these results demonstrate that Tat directly trans-activated XCL1 expression and suggest potential roles of Tat-induced XCL1 expression in the CNS infiltration of T lymphocytes during HIV-1 infection and subsequent HIV-1-induced neurological diseases.

Amino Acid Motifs↗
PubMed2001

Mammalian and viral IL-10 enhance C-C chemokine receptor 5 but down-regulate C-C chemokine receptor 7 expression by myeloid dendritic cells: impact on chemotactic responses and in vivo homing ability.

The immunosuppressive and anti-inflammatory cytokine IL-10 inhibits the phenotypic and functional maturation of dendritic cells (DC) and has been reported to confer tolerogenic properties on these important professional APC. Here, we exposed murine bone marrow-derived myeloid DC to either mouse (m) or viral (v) IL-10 early during their in vitro generation in response to GM-CSF and IL-4. Both mIL-10 and vIL-10 down-regulated the expression of CCR7 mRNA determined by RT-PCR, while mIL-10 up-regulated the expression of CCR5 transcripts. These changes in CCR7 and CCR5 expression were associated with inhibition and augmentation, respectively, of DC chemotaxis toward their respective agonists, macrophage inflammatory proteins 3beta and 1alpha, while in vivo homing of DC from peripheral s.c. sites to secondary lymphoid tissue of syngeneic or allogeneic recipients was significantly impaired. Anti-mIL-10R mAb reversed the effects of mIL-10 on CCR expression and restored DC homing ability. Retroviral transduction of mIL-10- and vIL-10-treated DC to overexpress transgenic CCR7 partially restored the cells' lymphoid tissue homing ability in allogeneic recipients. However, CCR7 gene transfer did not reinstate the capacity of IL-10-treated DC to prime host naive T cells for ex vivo proliferative responses or Th1 cytokine (IFN-gamma) production in response to rechallenge with (donor) alloantigen. These findings suggest that in addition to their capacity to subvert DC maturation/function and confer tolerogenic potential on these cells, mIL-10 and vIL-10 regulate DC migratory responses via modulation of CCR expression.

Adjuvants, Immunologic↗
PubMed1997

Production of the novel C-C chemokine MCP-4 by airway cells and comparison of its biological activity to other C-C chemokines.

Monocyte chemotactic protein-4 (MCP-4) is a newly identified C-C chemokine with potent eosinophil chemoattractant properties. We describe studies of its biological activity in vitro to induce chemotaxis of peripheral blood eosinophils and to induce histamine release from IL-3-primed peripheral blood basophils. MCP-4 and eotaxin caused a similar rise in eosinophil intracytoplasmic Ca2+ and complete cross-desensitization. MCP-4 also abolished the eosinophil Ca2+ response to MCP-3 and partially desensitized the response to macrophage inflammatory protein-1alpha. MCP-4 activated cell migration via either CCR2b or CCR3 in mouse lymphoma cells transfected with these chemokine receptors. MCP-4 inhibited binding of 125I-eotaxin to eosinophils and CCR3-transfected cells and inhibited 125I-MCP-1 binding to CCR2b-transfectants. MCP-4 mRNA was found in cells collected in bronchoalveolar lavage of asthmatic and nonasthmatic subjects and was prominently expressed in human lung and heart. MCP-4 mRNA was expressed in several human bronchial epithelial cell lines after cytokine stimulation. Pretreatment of BEAS-2B epithelial cells with the glucocorticoid budesonide inhibited MCP-4 mRNA expression. These features make MCP-4 a candidate for playing a role in eosinophil recruitment during allergic respiratory diseases.

Amino Acid Sequence↗
PubMedDate not supplied

Antiviral chemokines: intracellular life of recombinant C-C chemokine RANTES.

OBJECTIVE: Select C-C and C-X-C chemokines can suppress HIV infection. This is because their receptors are the gateways for HIV-1 entry, determinants of viral tropism and sensitivity. C-C chemokines are most effective against macrophage-tropic viruses, and C-X-C chemokines are most effective against T-tropic viruses. The epitopes on the chemokine molecule responsible for virus inhibition and for chemokines' specificities are not known. The objective of this study was to map the functional domains of prototypic antiviral chemokine, namely, RANTES (regulated-on-activation normal T-expressed and secreted). STUDY DESIGN: Optimal folding of the chemokine molecule is thought to be important for its biologic activity. Anticipating that it will provide a native milieu for folding, we expressed recombinant RANTES molecules in an HIV-2-derived lentivirus mammalian expression system. We focused on the structural landmarks of RANTES to determine their role in its life and function. RESULTS: We found that the flexible amino-terminal region of RANTES was not important for its structural integrity or antiviral activity, either positively or negatively. It was also not important for binding to the CCR5 receptor. Modification of all other domains was detrimental, implying a functional role. However, a more careful analysis revealed that these domains were crucial for controlling stability, transport, and secretion of the molecule. Although all recombinant clones contained signal sequence and were transcriptionally active, they presented three different phenotypes: normal synthesis and secretion, normal synthesis but blocked secretion, and presumed normal synthesis but rapid degradation. Structural considerations and preliminary experiments showing a lack of effect of proteasome inhibitors suggested that the signal recognition particle pathway of translocation and proteasomal pathway of destruction may not be the major determinant of the life of the chemokine. CONCLUSIONS: The amino-terminal domain of RANTES was not essential for its antiviral activity or for its binding to the CCR5 receptor. Although the 1-domain of the core and carboxy-terminal domain may contribute to the antiviral activity of RANTES, they were more important for its intracellular life.

Amino Acid Sequence↗
PubMed1996

Selective G protein coupling by C-C chemokine receptors.

The C-C chemokines are major mediators of chemotaxis of monocytes and some T cells in inflammatory reactions. The pathways by which the C-C chemokine receptors activate phospholipase C (PLC) were investigated in cotransfected COS-7 cells. The C-C chemokine receptor-1 (CKR-1), the MCP-1 receptor-A (MCP-1Ra), and MCP-1Rb can reconstitute ligand-induced accumulation of inositol phosphates with PLC beta2 in a pertussis toxin-sensitive manner, presumably through G beta gamma released from the Gi proteins. However, these three receptors demonstrated different specificity in coupling to the alpha subunits of the Gq class. While none of the receptors can couple to Galphaq/11, MCP-1Rb can couple to both Galpha14 and Galpha16, but its splicing variant, MCP-1Rb, cannot. Since MCP-1Ra and -b differ only in their C-terminal intracellular domains, the C-terminal ends of MCP-1Rs determine G protein coupling specificity. CKR-1 can couple to Galpha14 but not to Galpha16, suggesting some of the C-C chemokine receptors, unlike the C-X-C chemokine receptors, discriminate against Galpha16, a hematopoietic-specific Galpha subunit. The intriguing specificity in coupling of the Gq class of G proteins implies that the chemokines may be involved in some distinct functions in vivo. The commonality of the chemokine receptors in coupling to the Gi-Gbetagamma-PLC beta2 pathway provides a potential target for developing broad spectrum anti-inflammatory drugs.

Animals↗
PubMed1999

C-C chemokines in allergen-induced late-phase cutaneous responses in atopic subjects: association of eotaxin with early 6-hour eosinophils, and of eotaxin-2 and monocyte chemoattractant protein-4 with the later 24-hour tissue eosinophilia, and relationship to basophils and other C-C chemokines (monocyte chemoattractant protein-3 and RANTES).

The relationship of expression of the C-C chemokines eotaxin, eotaxin 2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4 to the kinetics of infiltrating eosinophils, basophils, and other inflammatory cells was examined in allergen-induced, late-phase allergic reactions in the skin of human atopic subjects. EG2+ eosinophils peaked at 6 h and correlated significantly with eotaxin mRNA and protein, whereas declining eosinophils at 24 h correlated significantly with eotaxin-2 and MCP-4 mRNA. In contrast, no significant correlations were observed between BB1+ basophil infiltrates, which peaked at 24 h, and expression of eotaxin, eotaxin-2, RANTES, MCP-3, and MCP-4 or elastase+ neutrophils (6-h peak), CD3+ and CD4+ T cells (24 h), and CD68+ macrophages (72 h). Furthermore, 83% of eosinophils, 40% of basophils, and 1% of CD3+ cells expressed the eotaxin receptor CCR3, while eotaxin protein was expressed by 43% of macrophages, 81% of endothelial cells, and 6% of T cells (6%). These data suggest that 1) eotaxin has a role in the early 6-h recruitment of eosinophils, while eotaxin-2 and MCP-4 appear to be involved in later 24-h infiltration of these CCR3+ cells; 2) different mechanisms may guide the early vs late eosinophilia; and 3) other chemokines and receptors may be involved in basophil accumulation of allergic tissue reactions in human skin.

Adolescent↗
PubMed1999

Neutrophil sequestration in liver and lung is differentially regulated by C-X-C chemokines during experimental peritonitis.

C-X-C chemokines play an important role in the migration and activation of neutrophils (PMNs) during an inflammatory event. We measured mRNA and protein expression of the murine C-X-C chemokines macrophage inflammatory protein-2 (MIP-2) and KC in the lungs, liver, blood, and peritoneal cavity of Swiss Webster mice after cecal ligation and puncture (CLP). Neutralizing antibodies to MIP-2 and KC were also used to determine the biological effects of these chemokines on neutrophil sequestration and organ injury in the CLP model. The data showed that early after CLP, MIP-2 mRNA and protein were expressed predominantly by the lung, whereas KC mRNA and protein were expressed by the liver. Inhibition of MIP-2 reduced both lung neutrophil sequestration and peritoneal neutrophil migration. Inhibition of KC had no effect on overall neutrophil sequestration in liver but reduced injury as measured by serum transaminases. An early survival benefit was found with anti-KC treatment, although overall survival was not different. Our study showed a differential expression by organs of C-X-C chemokines during sepsis and suggested that such chemokine effects are tissue-specific.

Animals↗
PubMed1997

Molecular cloning and characterization of a cDNA, CHEMR1, encoding a chemokine receptor with a homology to the human C-C chemokine receptor, CCR-4.

Chemokines refer to a rapidly expanding family of small cytokines whose primary function is recruitment of leukocytes to inflammatory sites. These are known to bind to seven-transmembrane-domain containing receptors. A cDNA clone, CHEMR1, resembling the typical G protein-coupled receptor, was isolated from a mouse cytotoxic T-lymphocyte (CTL) library. Northern blot analysis in mouse cell lines suggests that its expression is found in a variety of cells, including T cells, B cells, and macrophages. The CHEMR1 gene Scya3r2 is a single-copy gene whose open reading frame may be in a single exon and maps to the distal region of mouse Chr 9 where the mouse macrophage inflammatory protein-1alpha (MIP-1alpha) receptor gene Scya3r and two related C-C chemokine receptor-like genes reside. Amino acid sequence comparison shows that CHEMR1 is 84% identical to human CCR-4, indicating that CHEMR1 is likely to be a mouse CCR-4. Binding assays using 125I-labeled C-C chemokines in mammalian cells indicated that CHEMR1 did not bind MIP-1alpha, RANTES, or MIP-1beta, whereas CCR-1 binds MIP-1alpha and RANTES. Our result is different from the reported properties of human CCR-4. This suggests that CHEMR1 may be a receptor for unidentified C-C chemokine or a low-affinity receptor for MIP-1alpha.

Amino Acid Sequence↗
PubMed2002

Functional expression and characterization of macaque C-C chemokine receptor 3 (CCR3) and generation of potent antagonistic anti-macaque CCR3 monoclonal antibodies.

Eosinophils are major effector cells implicated in a number of chronic inflammatory diseases in humans, particularly bronchial asthma and allergic rhinitis. The beta-chemokine receptor C-C chemokine receptor 3 (CCR3) provides a mechanism for the selective recruitment of eosinophils into tissue and thus has recently become an attractive biological target for therapeutic intervention. In order to develop in vivo models of inflammatory diseases, it is essential to identify and characterize the homologues of human eotaxin (C-C chemokine ligand 11) and CCR3 from other species, such as non-human primates. Accordingly, we cloned the macaque eotaxin and CCR3 genes and revealed that they were 91 and 92% identical at the amino acid level to their human homologues, respectively. Macaque CCR3 expressed in the murine pre-B L1-2 cell line bound macaque eotaxin with high affinity (K(d) = 0.1 nm) and exhibited a robust eotaxin-induced Ca(2+) flux and chemotaxis. Characterization of beta-chemokines on native macaque CCR3 on eosinophils was performed by means of eotaxin-induced shape change in whole blood using a novel signaling assay known as gated autofluorescence forward scatter. Additionally, mAbs were raised against macaque CCR3 using two different immunogens: a 30-amino acid synthetic peptide derived from the predicted NH(2) terminus of macaque CCR3 and intact macaque CCR3-transfected cells. These anti-macaque CCR3 monoclonal antibodies exhibited potent antagonist activity in receptor binding and functional assays. The characterization of the macaque eotaxin/CCR3 axis and development of antagonistic anti-macaque CCR3 monoclonal antibodies will facilitate the development of CCR3 small molecule antagonists with the hope of ameliorating chronic inflammatory diseases in humans.

Amino Acid Sequence↗
PubMed1993

Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor.

The immunoregulatory proteins C-C chemokines are potent chemoattractants of lymphocytes and monocytes, as well as activators and attractants of eosinophils and basophils. We have isolated a cDNA that encodes a seven transmembrane-spanning receptor, with homology to other chemoattractant receptors, that encodes a protein designated C-C CKR-1 that acts as a receptor for the C-C chemokines. Human and murine macrophage inflammatory protein 1 alpha (MIP-1 alpha), human human monocyte chemotactic protein 1 (MCP-1), and RANTES all bind to the C-C CKR-1 with varying affinities. Chemokine binding affinity does not predict how well the ligand will transmit a signal through the receptor: RANTES and human MIP-1 alpha induce a similar intracellular calcium flux while binding with disparate affinities, while MCP-1 and human MIP-1 beta induce calcium mobilization only at high concentrations. Finally, C-C chemokines were shown to bind a C-C CKR-1-related gene product encoded by cytomegalovirus, suggesting a role for C-C chemokines in viral immunity.

Amino Acid Sequence↗
PubMed2000

Expression of C-C chemokines is associated with portal and periportal inflammation in the liver of patients with chronic hepatitis C.

Inflammation of the portal and periportal areas is a common feature of chronic hepatitis C. Antigen-presenting dendritic cells are located in the portal area, and infiltrating T cells are initially exposed to infected hepatocytes in the periportal area. Thus, these areas could be sites of the initial processes of the immune response in chronic hepatitis C. C-C chemokines (dendritic-cell-derived C-C chemokine [DC-CK1] and regulated upon activation, normal T-cell expressed and secreted [RANTES])-attracting T cells may play a role in the portal inflammatory changes. The relationship between the expression of these C-C chemokines, which attract T cells and the infiltration of T cells into the liver of patients with chronic hepatitis C, was examined by in situ hybridization and reverse transcription-polymerase chain reaction. T-cell activation was examined by immunostaining T-cell subsets. Specific signals were detected for DC-CK1 mRNA in mononuclear cells mainly in the portal area and for RANTES mRNA in the portal area and at sites of piecemeal necrosis in the liver of patients with chronic hepatitis C. Naive T cells were located mainly in the portal area, whereas active T cells were found mainly at sites of piecemeal necrosis in the periportal area. In addition, hepatic DC-CK1- and RANTES-mRNA levels were significantly correlated with serum alanine aminotransferase levels (p < 0.001). These results suggest that the local production of DC-CK1 and RANTES participates in immune responses by attracting naive and active T cells to the portal and periportal areas, respectively.

Actins↗
PubMed2002

Serum profiles of C-C chemokines in acute myocardial infarction: possible implication in postinfarction left ventricular remodeling.

C-C chemokines are essential factors in the recruitment and activation of leukocytes from the circulation into inflamed tissue and may play a role in ischemia-induced myocardial injury and left ventricular remodeling after acute myocardial infarction (AMI). We investigated the kinetics of three major C-C chemokines, macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1 alpha), and regulated on activation normally T cell expressed and secreted (RANTES), in the sera of AMI patients and correlated the findings with the severity of the disease. Serum levels of C-C chemokines were determined in 35 AMI patients by ELISA assays serially during the first week of hospitalization and 1 month after hospital admission. Patients (n = 18) with uncomplicated AMI (Killip class I) were classified as group A, patients (n = 17) with AMI complicated by heart failure manifestations (Killip classes II and III) were classified as group B, and 15 age-matched and sex-matched volunteers were used as healthy controls. A sustained increase in serum C-C chemokines was observed in both AMI groups during the 7-day hospitalization period. Peaks of these inflammatory factors were significantly higher in group B than in group A (MCP-1, 295 +/- 11 vs. 203 +/- 9 pg/ml, p < 0.01; MIP-1 alpha, 30 +/- 1 vs. 24 +/- 2 pg/ml, p < 0.05; RANTES, 32 +/- 2 vs. 16 +/- 1 ng/ml, p < 0.01) and healthy controls (MCP-1, 125 +/- 7 pg/ml, p < 0.001; MIP-1 alpha, 14 +/- 1 pg/ml, p < 0.001; RANTES, 12 +/- 1 ng/ml, p < 0.001). In group B, significant correlations were found between the peak of MCP-1 and the peak of C-reactive protein levels (r = 0.55, p < 0.02) as well as wedge pressure (r = 0.40, p < 0.05). In the same group, the peak of MIP-1 alpha levels was also significantly correlated with the peak of serum creatine kinase-myocardial band (MB) (r = 0.51, p < 0.04) and left ventricular ejection fraction (LVEF) (r = -0.45, p < 0.05). After 1 month, AMI patients (n = 14) with severe left ventricular dysfunction (LVEF < or = 35%) exhibited significantly higher levels of C-C chemokines (all p < 0.05) than the other AMI patients (n = 21) (LVEF > 35%). A significant correlation was found between MIP-1 alpha levels and left ventricular end-diastolic diameter (r = 0.47, p < 0.03) in this patient population. In conclusion, we have detected a significant elevation of major C-C chemokines during the course of AMI, with the highest levels in patients with AMI complicated by heart failure manifestations and severe left ventricular dysfunction. The elevation of these chemotactic inflammatory factors may actively contribute to the pathophysiology of the disease and the subsequent left ventricular remodeling.

Chemokine CCL2↗
PubMed2004

Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize mu-opioid receptors on dorsal root ganglia neurons.

Pain is one of the hallmarks of inflammation. Opioid receptors mediate antipain responses in both the peripheral nervous system and CNS. In the present study, pretreatment of CCR1: mu-opioid receptor/HEK293 cells with CCL3 (MIP-1alpha) induced internalization of mu-opioid receptors and severely impaired the mu-opioid receptor-mediated inhibition of cAMP accumulation. Immunohistochemical staining showed that CCR1 and mu-opioid receptors were coexpressed on small to medium diameter neurons in rat dorsal root ganglion. Analysis of ligand-induced calcium flux showed that both types of receptors were functional. Pretreatment of neurons with CCL3 exhibited an impaired [D-Ala(2),N-MePhe(4),Gly-o15]enkephalin-elicited calcium response, indicative of the heterologous desensitization of mu-opioid receptors. Other chemokines, such as CCL2, CCL5, and CXCL8, exhibited similar inhibitory effects. Our data indicate that proinflammatory chemokines are capable of desensitizing mu-opioid receptors on peripheral sensory neurons, providing a novel potential mechanism for peripheral inflammation-induced hyperalgesia.

Animals↗