Asthma is a chronic inflammatory respiratory disease accompanied with airway inflammation, airway remodeling and bronchial hyperresponsiveness. Chemokines are important for the recruitment of immune cells to the lung, which play an important role in the formation and development of asthma. Targeting the chemokine receptors to anti-inflammation and anti-asthma is a new strategy and some candidate drugs are discovered recently. This review is focused on the development of chemokine receptor antagonists for anti-asthma, which will promote the compound designations.
Animals ; Anti-Asthmatic Agents ; pharmacology ; therapeutic use ; Asthma ; drug therapy ; Heterocyclic Compounds ; pharmacology ; Humans ; Phenylurea Compounds ; therapeutic use ; Piperidines ; pharmacology ; therapeutic use ; Pyridazines ; pharmacology ; Receptors, CCR1 ; antagonists & inhibitors ; Receptors, CCR3 ; antagonists & inhibitors ; Receptors, CCR4 ; antagonists & inhibitors ; Receptors, CXCR4 ; antagonists & inhibitors ; Receptors, Chemokine ; antagonists & inhibitors

BACKGROUND AND OBJECTIVES: CC chemokine receptor (CCR5) is characteristic of the Th 1 phenotype, the receptor of RANTES, MIP-1alphaand MIP-1beta. The receptor of CCR5 delta32 (a 32 bp deletion in the CCR5 gene, mutant type) results in the production of a non-functional receptor. Given the potential importance of CCR5 in allergic inflammation, we hypothesized that individuals carrying the CCR5 delta32 allele would show a reduced prevalence of allergic rhinitis. SUBJECTS AND METHOD: Blood samples for genetic analysis were obtained from 187 individuals with allergic rhinitis and from 278 healthy subjects without atopic diseases. Polymerase chain reaction-based assay for the CCR5 gene polymorphism was used for genotyping. RESULTS: We could not find the CCR5 delta32 homozygotes and heterozygotes at all in neither of the controls nor allergic rhinitis Korean patients. CONCLUSION: Since the CCR5 delta32 allele frequency did not deviate from that in the healthy control population, it is unlikely that this allele influences predisposition to allergic rhinitis in Koreans.
Alleles ; Asian Continental Ancestry Group ; Chemokine CCL4 ; Chemokine CCL5 ; Gene Frequency ; Heterozygote ; Homozygote ; Humans ; Inflammation ; Phenotype ; Prevalence* ; Receptors, CCR ; Receptors, CCR5 ; Rhinitis*

The exact pathogenesis of nasal polyposis is unknown, but inflammation is thought to be an important factor in its development. CC chemokines and CC chemokine receptors on inflammatory cells influence the cells' migration to the inflammation sites. In an attempt to better understand the events of this migration, we performed an analysis of the CC chemokine receptors mRNA in nasal polyps, allergic inferior turbinate mucosa and hypertrophic inferior turbinate mucosa. The expression of CC chemokine receptor mRNA was measured with an RT-PCR in 20 samples of nasal polyps, seven samples of allergic inferior turbinate mucosa and six samples of hypertrophic inferior turbinate mucosa. The results showed the expression levels of CCR2, CCR3, CCR4, and CCR5 mRNA to be higher in the nasal polyps than in the mucosa taken from the allergic and hypertrophic inferior turbinates. CCR4 and CCR5 mRNA expressed more strongly than did CCR1, CCR2 and CCR3 mRNA (p<0.001). The number of infiltrating eosinophils correlated with the level of CCR3 mRNA expression (p<0.001).
Chemokines, CC ; Eosinophils* ; Inflammation ; Mucous Membrane* ; Nasal Polyps* ; Receptors, CCR* ; RNA, Messenger* ; Turbinates*

Endometriosis ; etiology ; metabolism ; Environmental Pollution ; Female ; Hormones ; metabolism ; Humans ; Receptors, CCR ; metabolism

This study was purposed to explore the correlation of CXCR4, CCR1, CCR2 expression with curative effect of multiple myeloma (MM). Flow cytometry was used to detect the expressions of CXCR4, CCR1, CCR2 on cell surface of bone marrow from 48 newly diagnosed MM patients. These patients were divided into two groups: one group with expression of chemokine receptor (group I) and another group without expression of chemokine receptor (group II). The group I was consisted of 34 patients, but 3 out of them could not be continuously followed up. The group II was consisted of 14 patients. The MM patients of 2 groups were treated with chemotherapeutic drugs for 3 and 6 months, the curative efficacy of 2 groups were compared. The results showed that after treating for 3 and 6 months the effective rates of group I and group II were 80.6% (25/31) vs 50% (7/14) and 83.9% (26/31) vs 50% (7/14) respectively, which suggested that curative efficacy of group I was better than that of group II (p < 0.05). It is concluded that CXCR4, CCR1, CCR2 may be used as indexes for evaluating curative effect of MM patients.
Adult ; Aged ; Aged, 80 and over ; Female ; Flow Cytometry ; Humans ; Male ; Middle Aged ; Multiple Myeloma ; drug therapy ; metabolism ; Receptors, CCR1 ; metabolism ; Receptors, CCR2 ; metabolism ; Receptors, CXCR4 ; metabolism ; Treatment Outcome

BACKGROUND: Chemokines and their receptors are important players in tumorigenesis by facilitating tumor proliferation and metastasis. Little is known about the possible function of chemokine receptors in relation to the development and progression of malignant cutaneous tumors. OBJECTIVE: The aim of this study was to determine the chemokine receptor CCR3 expression pattern and the protein expression level in selected malignant cutaneous tumors. METHODS: Four types of cell lines (G361, A431, SK-MEL-2, SK-MEL-24) were analyzed, using Western blotting, for the expression of CCR3 protein. Immunohistochemical staining for CCR3 was done on 36 skin cancer tissue samples that included 16 squamous cell carcinomas (SCCs), 16 basal cell carcinomas (BCCs), 16 malignant melanomas (MMs) and 6 normal tissue samples. RESULTS: Western blot analysis showed that CCR3 protein was more expressed in the MM cell lines (G361, SK-MEL-2,SK-MEL-24) than that in the SCC cell line (A431), and the immunohistochemical analysis showed that CCR3 protein was overexpressed in MM and SCC, it was mildly expressed in BCC and it was hardly expressed in normal tissue. CONCLUSION: This study demonstrated via immunochemistry that CCR3 was more expressed in MM, followed by SCC and BCC. The existence of CCR3 protein may enhance the tumorigenic potential of malignant cutaneous tumors.
Blotting, Western ; Carcinoma, Basal Cell ; Carcinoma, Squamous Cell ; Cell Line ; Cell Transformation, Neoplastic ; Chemokines ; Immunochemistry ; Melanoma ; Neoplasm Metastasis ; Receptors, CCR ; Receptors, Chemokine ; Skin Neoplasms

This study was aimed to explore the expression of MIP-1alpha, MCP-1 and their receptors CCR-1, CCR-2 in bcr/abl fusion gene positive CML cells, and to study the effects of P210(bcr/abl) fusion protein tyrosine kinase on expression of MIP-1alpha, MCP-1 and their receptors CCR-1, CCR-2 mRNAs in chronic myeloid leukemia cells. The expression levels of MIP-1alpha, MCP-1 and their receptors CCR-1, CCR-2 mRNA were detected by semi-quantitative RT-PCR in bcr/abl negative cells, bcr/abl positive cells, and P210(bcr/abl)-Rb-C-Box positive cells. The results showed that MIP-1alpha and CCR-1 mRNAs were expressed in bcr/abl negative cells, but not in positive cells. Both MCP-1 and CCR-2 mRNA cannot be detected in both bcr/abl positive and negative cells. After inhibiting P210(bcr/abl) tyrosine kinase activity by Rb-C-Box, expressions of MIP-1alpha and CCR-1 mRNAs were restored to normal (similar to P210(bcr/abl) negative cells). It is concluded that P210(bcr/abl) fusion protein inhibits the expression of MIP-1alpha and CCR-1 in chronic myeloid leukemia cells, but does not inhibit MCP-1 and CCR-2 mRNA expressions in these leukemia cells.
Chemokine CCL2 ; biosynthesis ; genetics ; Chemokine CCL3 ; Chemokine CCL4 ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; metabolism ; Macrophage Inflammatory Proteins ; biosynthesis ; genetics ; Receptors, CCR1 ; Receptors, CCR2 ; Receptors, Chemokine ; biosynthesis ; genetics ; Tumor Cells, Cultured

BACKGROUND: CC chemokine receptor (CCR) 7 and cognate CCR7 ligands, CCL21 (formerly secondary lymphoid tissue chemokine [SLC]) and CCL19 (formerly Epstein-Barr virus-induced molecule 1 ligand chemokine [ELC]), were known to establish microenvironment for the initiation of immune responses in secondary lymphoid tissue. As described previously, coadministration of DNA vaccine with CCR7 ligand-encoding plasmid DNA elicited enhanced humoral and cellular immunity via increasing the number of dendritic cells (DC) in secondary lymphoid tissue. The author hypothesized here that CCR7 ligand DNA could effectively expand memory CD4+ T cells to protect from viral infection likely via increasing DC number. METHODS: To evaluate the effect of CCR7 ligand DNA on the expansion of memory CD4+ T cells, DO11.10.BALB/c transgenic (Tg)-mice, which have highly frequent ovalbumin (OVA)(323-339) peptide-specific CD4+ T cells, were used. Tg-mice were previously injected with CCR7 ligand DNA, then immunized with OVA(323-339) peptide plus complete Freund's adjuvant. Subsequently, memory CD4+ T cells in peripheral blood lymphocytes (PBL) were analyzed by FACS analysis for memory phenotype (CD44(high) and CD62(Llow)) at memory stage. Memory CD4+ T cells recruited into inflammatory site induced with OVA-expressing virus were also analyzed. Finally, the protective efficacy against viral infection was evaluated. RESULTS: CCR7 ligand DNA-treated Tg-mice showed more expanded CD44(high) memory CD4+ T cells in PBL than control vector-treated animals. The increased number of memory CD4+ T cells recruited into inflammatory site was also observed in CCR7 ligand DNA-treated Tg-mice. Such effectively expanded memory CD4+ T cell population increased the protective immunity against virulent viral infection. CONCLUSION: These results document that CCR7 and its cognate ligands play an important role in intracellular infection through establishing optimal memory T cell. Moreover, CCR7 ligand could be useful as modulator in DNA vaccination against viral infection as well as cancer
Animals ; Chemokine CCL19 ; Chemokine CCL21 ; Dendritic Cells ; DNA ; Freund's Adjuvant ; Immunity, Cellular ; Ligands* ; Lymphocytes ; Lymphoid Tissue ; Memory* ; Ovalbumin ; Phenotype ; Plasmids ; Receptors, CCR ; T-Lymphocytes* ; Vaccination

Chemokines and chemokine receptors play a role in migration of circulating leukocytes to the region of inflammation. Human LZIP is an uncharacterized transcription factor and is known to participate in leukotactin (Lkn)-1/CCL15-induced cell migration. We investigated the role of human LZIP in expression of CC chemokine receptors (CCRs) and its involvement in monocyte migration. RNase protection analysis showed that LZIP increased mRNA expression of CCR2 and CCR1 in THP-1 cells. Surface expressions of both CCR2 and CCR1 were also increased by LZIP. Results from an electrophoretic mobility shift assay showed that LZIP binds to the C/EBP element in the CCR2 promoter. LZIP also enhanced the chemotactic activities of monocyte chemoattractant protein-1/CCL2 and Lkn-1. These results suggest that LZIP regulates expression of chemokine receptors that are involved in monocyte migration.
Atherosclerosis/drug therapy/etiology ; CCAAT-Enhancer-Binding Proteins/genetics/immunology/*metabolism ; Cell Line, Tumor ; Cell Movement/drug effects/*physiology ; Chemokine CCL2/*pharmacology ; Chemokines, CC/pharmacology ; Cyclic AMP Response Element-Binding ; Humans ; Macrophage Inflammatory Proteins/pharmacology ; Monocytes/drug effects/metabolism ; Promoter Regions, Genetic ; Protein Binding ; RNA, Messenger/analysis ; Receptors, CCR1/biosynthesis/genetics ; Receptors, CCR2/*biosynthesis/genetics ; Transcriptional Activation/drug effects ; Transfection ; Transgenes

OBJECTIVETo explore the association of CCR5δ32, CCR2-64I and SDFl-3 A gene polymorphisms with HIV-1-infection in Chinese population.

METHODSA meta-analysis was performed to identify case-control studies of CCR5δ32, CCR2-64I and SDFl-3 A polymorphisms from the literatures.

RESULTSFourteen studies of CCR5δ32 were found, involving a total of 1607 cases and 1632 controls. Compared with the wild-type homozygote wt/wt, the pooled odds ratios (95%CI) of wt/mt, mt/mt, and wt/mt+mt/mt genotypes of CCR5δ32 gene polymorphisms were 1.156 (0.808, 1.654), 0.997 (0.198, 5.022), and 1.149 (0.808, 1.634), respectively. Twelve studies of CCR2-64I were identified, including 1415 cases and 1239 controls. Compared with the wild-type homozygote wt/wt, the pooled odds ratios (95%CI) of wt/mt, mt/mt, and wt/mt+mt/mt genotypes of CCR2-64I gene polymorphisms were 1.005 (0.844, 1.197), 1.191 (0.808, 1.754), and 1.028 (0.870, 1.214), respectively. Ten studies of SDFl-3 A were found, involving 1179 cases and 1003 controls. Compared with the wild-type homozygote wt/wt, the pooled odds ratios (95%CI) of wt/mt, mt/mt, and wt/mt + mt/mt genotypes of SDF1-3 A gene polymorphisms were 1.010 (0.830, 1.228), 1.188 (0.860, 1.643), and 1.038 (0.861, 1.250).

CONCLUSIONCCR5δ32, CCR2-64I and SDFl-3 A gene polymorphisms do not show strong correlations to HIV-1-infection in Chinese population. These 3 genes may not have protective effect against HIV-1 infection in Chinese population, suggesting the susceptibility of Chinese population to the infection.

Alleles ; Asian Continental Ancestry Group ; genetics ; Chemokine CXCL12 ; genetics ; Gene Frequency ; Genotype ; HIV Infections ; genetics ; HIV-1 ; Humans ; Polymorphism, Genetic ; Receptors, CCR2 ; genetics ; Receptors, CCR5 ; genetics