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PubMed1996

Activation of NK cells by CC chemokines. Chemotaxis, Ca2+ mobilization, and enzyme release.

The responses of cloned human NK cells (ERNK57) to seven CC chemokines (monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3, RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein-1 alpha (MIP-1 alpha), MIP-1 beta, and 1309) and two CXC chemokines (IL-8 and IP-10) were studied. Except for 1309, all CC chemokines induced chemotaxis of the NK cells in vitro, whereas the CXC chemokines were inactive. Maximal activity was obtained at 1 nM for MCP-1 and 10 to 100 nM for the other CC chemokines. The response showed a typically bimodal concentration dependence in all cases, except for RANTES, which induced a linear increase of migration over the concentration range of 0.1 to 1000 nM. A transient rise of the cytosolic-free Ca2+ concentration ([Ca2+]i), which is characteristic for chemokine-stimulated leukocytes, was observed in NK cells after stimulation with all six active chemokines. Since granule exocytosis is required for NK cell-dependent target killing, the effect of CC chemokines on exocytosis was tested. All CC chemokines that induced chemotaxis and [Ca2+]i changes also induced the release of granzyme A and N-acetyl-beta-D-glucosaminidase from cloned and blood NK cells, as well as CD8+ T cells after pretreatment with cytochalasin B. Maximum release was obtained from NK cells, and amounted to 35% and 13% of the total content of granzyme A and N-acetyl-beta-D-glucosaminidase, respectively. The capacity of cloned NK cells and CD8+ T cells to respond to chemokines depended on the time in culture after stimulation with PHA in the presence of irradiated feeder cells, and maximum responses were observed after 10 to 16 days. Our results demonstrate that CC chemokines activate NK cells, and are, therefore, not only attractants for monocytes, T lymphocytes, and eosinophil and basophil granulocytes.

Calcium↗

PubMedDate not supplied

Central action of insect neuropeptide, periplanetin CC-1, in mice.

The central action of periplanetin CC-1 (Pea-HrTH) (Glp-Val-Asn-Phe-Ser-Pro-Asn-TrpNH2), octapeptide of the insect adipokinetic hormone family (AKH-family), isolated from American cockroach-Periplaneta americana, was studied in Albino Swiss mice (20-25 g). CC-1 was injected intracerebroventricularly (i.c.v.) in the volume of 5 microliters at the dose of 50 ng/mouse. It was found that CC-1 showed strong analgesic activity in "writhing syndrome" test and in "hot plate" test. In addition, periplanetin CC-1 decreased the threshold for tonic seizures and increased mortality in pentetrazole-induced seizures, having no influence on the electric convulsions. CC-1 is known to be a glucagon-like AKH in insects. However, administered i.c.v. to mice, it did not increase the peripheral blood glucose level. The obtained results indicate that periplanetin CC-1 shows a biological action in vertebrates, but its metabolic effects are different than in insects.

Animals↗

PubMed1997

Novel lymphocyte-specific CC chemokines and their receptors.

By using a cloning method termed the signal sequence trap as well as by searching for chemokine homologous sequences in the database of expressed sequence tags, cDNA fragments potentially encoding novel CC chemokines were initially identified. Using these sequences, we have cloned five novel human CC chemokines termed TARC, LARC, ELC, SLC, and PARC. These chemokines are constitutively expressed especially in some lymphoid tissues with individually unique expression patterns. The recombinant proteins are all found to be selectively chemotactic for lymphocytes but not for monocytes or neutrophils. Each chemokine appears to interact with a class of receptors on lymphocytes that is not shared by any other chemokines so far tested. Furthermore, we have identified CCR4 as the specific receptor for TARC, GPR-CY4/DRY6/CKR-L3/STRL22 as that for LARC (CCR6), and EBI1/BLR2 as that for ELC (CCR7). Only the gene for PARC is mapped to the traditional CC chemokine gene cluster at chromosome 17q11.2, whereas those for TARC, LARC, ELC, and SLC are localized at different loci. Collectively, these five CC chemokines may constitute a new category of CC chemokines that are involved in trafficking and homing of particular subsets of lymphocytes in particular lymphoid tissue microenvironments.

Amino Acid Sequence↗

PubMed2000

Cloning, characterization and genomic organization of LCC-1 (scya16), a novel human CC chemokine expressed in liver.

By homology search of expressed sequence tags (EST) in GenBank a novel member of the CC chemokine family was identified. The full-length sequence of this liver-specific CC chemokine (LCC-1) predicted a mature protein of 97 amino acids with 31-48% identity to other CC chemokines. There was a characteristic amino acid C-term extension when aligned with other chemokines. Northern blot analysis from a panel of human tissues revealed that LCC-1 mRNA expression is restricted to adult and fetal liver. Different polyadenylation results in two mRNA species of 1.5 kb and 0.5 kb in size. LCC-1 is constitutively expressed in human HepG2 hepatoma cells and is induced by hypoxic exposure. The promoter region of the LCC-1 gene contains potential HIF-1 binding sites. The EST for LCC-1 has been previously mapped to the CC chemokine cluster on human chromosome 17q11.2. The organization of the LCC-1 gene (scya16) into three exons interrupted by two introns is identical to that found for other members of the CC chemokine family.

Adult↗

PubMed2005

In silico identification and expression analysis of 12 novel CC chemokines in catfish.

Chemokines, a superfamily of chemotactic cytokines involved in recruitment, activation, and adhesion of a variety of leukocyte types to inflammatory foci, are a crucial component of the immune system of Sarcopterygiian vertebrates. Although all mammalian chemokines are believed to have been found, the status of these molecules in Actinopterygii was unknown until recently. The identification of chemokines in fish species has been complicated by low sequence conservation and confusion over expected numbers. Earlier discoveries of single fish chemokines coupled with rapidly expanding genetic resources in these species have recently provided a foundation for large-scale in silico discoveries of these important immune regulators. We report here the identification and expression analysis of 12 new CC chemokine sequences from catfish. When added to our previous report of 14 catfish CC chemokines, the number of CC chemokines in catfish now stands at 26, two more than known from humans. Establishing orthologous relationships among the majority of catfish CC chemokines, a newly available set of chicken CC chemokines, and their mammalian counterparts remain difficult, suggesting high levels of duplication and divergence within individual species.

Amino Acid Sequence↗

PubMed2003

CC chemokines induce P-selectin-dependent neutrophil rolling and recruitment in vivo: intermediary role of mast cells.

1. Based on in vitro chemotaxis experiments, it is widely held that CC chemokines, such as macrophage inflammatory protein-1alpha (MIP-1alpha) and macrophage chemotactic protein-1 (MCP-1) mainly support lymphocyte trafficking. 2. The objective of the present study was to examine the role of MIP-1alpha and MCP-1 in neutrophil recruitment in vivo by use of intravital microscopy of the mouse cremaster microcirculation. 3. MIP-1alpha and MCP-1 caused a dose-dependent increase in leukocyte rolling, adhesion and recruitment. Indeed, neutrophils comprised more than 85% of the leukocyte response to MIP-1alpha and MCP-1. An anti-P-selectin antibody reduced MIP-1alpha and MCP-1-provoked leukocyte rolling by more than 94%. Concomitantly, firm adhesion and extravasation of neutrophils in response to MIP-1alpha and MCP-1 challenge were significantly decreased by more than 78 and 84%, respectively. In contrast, an anti-E-selectin antibody had no influence on CC chemokine-induced neutrophil recruitment. 4. Flow cytometric analysis revealed that MIP-1alpha and MCP-1 had no effect on P-selectin expression on endothelial cells, suggesting that neutrophil recruitment elicited by CC chemokines in vivo is not mediated via a direct effect on the endothelium but rather via an indirect effect involving activation of an intermediary tissue cell. Indeed, it was found that MIP-1alpha-induced neutrophil accumulation was significantly decreased by 58% in mast cell-deficient mice. 5. These findings demonstrate that CC chemokines trigger P-selectin-dependent rolling and tissue recruitment of neutrophils via tissue mast cells in vivo and suggest that CC chemokines may also be important targets in neutrophil-mediated tissue damage in multicellular organs.

Animals↗

PubMed2001

Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours.

To understand the chemokine network in a tissue, both chemokine and chemokine receptor expression should be studied. Human epithelial ovarian tumours express a range of chemokines but little is known about the expression and localisation of chemokine receptors. With the aim of understanding chemokine action in this cancer, we investigated receptors for CC-chemokines and their ligands in 25 biopsies of human ovarian cancer. CC-chemokine receptor mRNA was generally absent from solid tumours, the exception being CCR1 which was detected in samples from 75% of patients. CCR1 mRNA localised to macrophages and lymphocytes and there was a correlation between numbers of CD8(+) and CCR1 expressing cells (P = 0.031). mRNA for 6 CC-chemokines was expressed in a majority of tumour samples. In a monocytic cell line in vitro, we found that CCR1 mRNA expression was increased 5-fold by hypoxia. We suggest that the CC-chemokine network in ovarian cancer is controlled at the level of CC-chemokine receptors and this may account for the phenotypes of infiltrating cells found in these tumours. The leukocyte infiltrate may contribute to tumour growth and spread by providing growth survival factors and matrix metalloproteases. Thus, CCR1 may be a novel therapeutic target in ovarian cancer.

Adenocarcinoma, Clear Cell↗

PubMed2001

Regulatory effect of histamine H1 receptor antagonist on the expression of messenger RNA encoding CC chemokines in the human nasal mucosa.

BACKGROUND: Allergic rhinitis is characterized by tissue accumulation of inflammatory cells. CC chemokines, including monocyte chemotactic protein (MCP) 1, MCP-3, RANTES, and eotaxin, are thought to play an important role in inducing selective recruitment of these cells to the allergic inflammatory site. Furthermore, MCPs have been indicated as histamine-releasing factors. Histamine is an important mediator in the pathogenesis of nasal allergy. The regulation of histamine may have a role in the management of allergic inflammation. OBJECTIVE: The objectives of this study were to investigate the expression of MCP-1, MCP-3, RANTES, and eotaxin in the nasal mucosa of patients with allergic rhinitis and to clarify the effect of histamine and antihistamine on the regulation of the expression of these CC chemokines. METHODS: By using a semiquantitative reverse transcriptase PCR technique, the numbers of copies of messenger RNA encoding MCP-1, MCP-3, RANTES, and eotaxin were measured in explant cultures of human nasal mucosa. In culture medium, specific antigen or histamine was added. Furthermore, the effect of preincubation with the antihistamine carebastine was estimated. RESULTS: Mite antigen (1:2 x 10(4) dilution) and histamine (10(-4) to 10(-3) mol/L) upregulated the messenger RNA expression of these CC chemokines at 3- to 10-fold increases. Carebastine (10(-7) to 10(-6) mol/L) inhibited this upregulation. CONCLUSION: Our results suggest that histamine may induce CC chemokine production in the nasal mucosa of patients with allergic rhinitis. This indicates that there may be a prolonged inflammatory cycle in the histamine-MCP axis in allergic rhinitis. The regulation of histamine-CC chemokine interaction could lead to new therapeutic approaches in the treatment of nasal allergy.

Adult↗

PubMed1999

Genomic organization of the genes for human and mouse CC chemokine LEC.

Liver-expressed chemokine (LEC) is a CC chemokine that is selectively expressed in the liver. We report here the structures of the human and mouse genes for LEC. The human LEC gene (SCYA16) was isolated from a bacterial artificial chromosome (BAC) clone that also contained CC chemokine genes for MPIF-1/Ckbeta8, HCC-2/Lkn-1/MIP-5/MIP-1delta, and HCC-1. The LEC gene is approximately 5.0 kb in length and has a three-exon and two-intron structure common to most CC chemokine genes. However, the promoter region is devoid of a typical TATA box, and transcription initiates at multiple sites. The gene for CC chemokine HCC-1, which is most similar to LEC, is located approximately 2.2 kb upstream from the 5' end of the LEC gene in a head-to-tail fashion. The mouse DNA fragment that hybridized with the human LEC cDNA was isolated from a BAC clone that also contained the CC chemokine genes for C10, MRP-2/CCF18/MIP-1gamma, and RANTES. Sequence analysis revealed that the isolated gene does not encode a functional chemokine because of deletions, insertions, and base changes. Southern blot analysis revealed that the sequence isolated from the BAC clone was the only one hybridizing with human LEC cDNA in the mouse genome. Therefore, mice may have only an LEC pseudogene.

Adolescent↗

PubMed2003

Comparative DNA sequence analysis of mouse and human CC chemokine gene clusters.

The CC chemokines are a closely related subfamily of the chemokine superfamily. Most of the CC chemokine genes form a cluster on chromosome 11 in mice and chromosome 17 in humans. To date, 11 and 16 functional genes have been localized within the mouse and human clusters, respectively. Notably, some of the genes within these clusters appear to have no counterparts between the two species, and the orthologous relationships of some of the genes are difficult to establish solely on the basis of amino acid similarity. In this study, we have taken a comparative genomic approach to reveal some of the features that may be involved in the dynamic evolution of these gene clusters. We sequenced a 122-kb region containing five chemokine genes of the mouse CC cluster. This mouse sequence was combined with those determined by the Mouse Genome Sequencing Project, and the entire sequence of the mouse CC cluster was compared with that of the corresponding cluster in the human genome by percent identity plot and dot-plot analyses. Although no additional chemokine genes have been found in these clusters, our analysis has revealed that numerous gene rearrangements have occurred even after the diversification of rodents and primates, resulting in several species-specific chemokine genes and pseudogenes. In addition, phylogenetic analysis and comparison of the genomic sequences unambiguously identified the orthologous relationships of some of the chemokine genes in the mouse and human CC gene clusters.

Animals↗

PubMed2006

Long-term erythropoietin therapy decreases CC-chemokine levels and intima-media thickness in hemodialyzed patients.

BACKGROUND: CC-chemokines are now widely accepted in the recruitment of leukocytes from the blood compartment into tissues, and their role in the progression of atherosclerosis has been documented. Recombinant human erythropoietin (EPO) has become widely used to treat anemic HD patients. However, little is known about the effect of EPO on the plasma CC-chemokine levels and intima-media thickness (IMT) in HD patients. METHODS: Assessment of CC-chemokines: monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1alpha, MIP-1beta), regulated upon activation, normal T cell expressed and secreted (RANTES) and IMT were performed in 26 stable HD patients and 15 healthy controls. The patients were divided into 3 groups: group I (n = 8, without EPO), group II (n = 9, EPO at a mean dose of 76 +/- 48 U/kg/week for more than 4 months), and group III (n = 9, EPO at a mean dose of 110.5 +/- 21 U/kg/week for more than 12 months), none of them on iron therapy. RESULTS: MCP-1, MIP-1alpha, MIP-1beta and IMT values were significantly higher, whereas RANTES were significantly lower in HD patients without EPO therapy than those in healthy controls. CC-chemokine levels were found to be significantly lower in patients administered EPO when compared to subjects without EPO. In the patients treated with EPO for more than 12 months IMT values were significantly decreased compared to patients not receiving this hormone. CONCLUSION: These results suggest that long-term EPO therapy decreased CC-chemokine and IMT values in patients undergoing regular HD in the absence of concomitant iron supplementation.

Atherosclerosis↗

PubMed2001

Identification of a blood-derived chemoattractant for neutrophils and lymphocytes as a novel CC chemokine, Regakine-1.

Chemokines constitute a large family of chemotactic cytokines that selectively attract different blood cell types. Although most inflammatory chemoattractants are only induced and released in the circulation during acute infection, a restricted number of CXC and CC chemokines are constitutively present in normal plasma at high concentrations. Here, such a chemotactic protein was purified to homogeneity from serum and fully identified as a novel CC chemokine by mass spectrometry and amino acid sequence analysis. The protein, tentatively designated Regakine-1, shows less than 50% sequence identity with any known chemokine. This novel CC chemokine chemoattracts both neutrophils and lymphocytes but not monocytes or eosinophils. Its modest chemotactic potency but high blood concentration is similar to that of other chemokines present in the circulation, such as hemofiltrate CC chemokine-1, platelet factor-4, and beta-thromboglobulin. Regakine-1 did not induce neutrophil chemokinesis. However, it synergized with the CXC chemokines interleukin-8 and granulocyte chemotactic protein-2, and the CC chemokine monocyte chemotactic protein-3, resulting in an at least a 2-fold increase of the neutrophil and lymphocyte chemotactic response, respectively. The biologic effects of homogeneous natural Regakine-1 were confirmed with chemically synthesized chemokine. Like other plasma chemokines, it is expected that Regakine-1 plays a unique role in the circulation during normal or pathologic conditions.

Amino Acid Sequence↗

PubMed2005

CCR5 expression and CC chemokine levels in idiopathic pulmonary fibrosis.

CC chemokines play an important role in the pathogenetic mechanisms of interstitial lung disease, while a downregulation of CC chemokine receptor (CCR)5 in the fibrotic stages of sarcoidosis has been observed. To evaluate the involvement of CC chemokines and the expression of CCR5 in idiopathic pulmonary fibrosis (IPF) and, more specifically, in usual interstitial pneumonia, 35 subjects were studied. CC chemokine ligand (CCL)2, CCL3 and CCL4 levels were measured in the bronchoalveolar lavage fluid (BALF) of 18 nonsmoker control subjects and 17 patients affected by IPF. CCR5 expression was evaluated in alveolar macrophages and lymphocytes. The BALF levels of all chemokines were significantly increased in IPF: median (range) CCL3 1.6 (1.0-11.1) versus 1.2 (0.0-3.8) pg x mL(-1); CCL4 6.2 (1.3-96.0) versus 3.4 (0.3-6.8) pg x mL(-1); and CCL2 60.1 (16.7-251.3) versus 4.6 (0.5-119.4) pg x mL(-1). CCL2 levels correlated negatively with the carbon monoxide diffusing capacity of the lung (D(L,CO)) and arterial oxygen tension. CCR5 expression was significantly reduced in lymphocytes from IPF compared with controls. The CC chemokines investigated are involved in the inflammatory mechanisms of idiopathic pulmonary fibrosis, and the results are in agreement with the hypothesis of a downregulation of the T-helper 1 immunological response in this disease.

Bronchoalveolar Lavage Fluid↗

PubMed2001

Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes.

The infiltration of leukocytes plays a major role in mediating tubulointerstitial inflammation and fibrosis in chronic renal disease. CC chemokines participate in leukocyte migration and infiltration into inflamed renal tissue. Because CC chemokine-directed leukocyte migration is mediated by target cell expression of a group of CC chemokine receptors, this study examined the expression of CC chemokines and their receptors during initiation of tubulointerstitial fibrosis after unilateral ureteral obstruction in C57BL/6 mice. Obstructed kidneys developed hydronephrosis, tubular cell damage, interstitial inflammation, and fibrosis. From days 2 to 10, a progressive interstitial influx of F4/80+ macrophages and CD3+ lymphocytes occurred (macrophages, 4-fold; lymphocytes, 20-fold at day 10, compared with contralateral control kidneys). In parallel, the number of activated fibroblast-specific protein 1+ fibroblasts and interstitial collagen IV accumulation increased from days 2 to 10. The mRNA expression of CC chemokines (predominantly monocyte chemoattractant protein-1 [MCP-1]/CCL2, RANTES/CCL5) and their receptors CCR1, CCR2, CCR5 increased progressively from days 2 to 10. By in situ hybridization, a prominent interstitial mRNA expression of MCP-1 and RANTES and their receptors CCR2 and CCR5 localized to interstitial mononuclear cell infiltrates. MCP-1 and RANTES expression was also seen in tubular epithelial cells. Fluorescence-activated cell sorter analysis of single-cell suspensions from obstructed kidneys revealed a prominent expression of CCR2 and CCR5 by infiltrating macrophages, whereas most lymphocytes expressed CCR5 only. These data demonstrate an increased expression of MCP-1/CCL2 and RANTES/CCL5 at sites of tubulointerstitial damage and progressive fibrosis during unilateral ureteral obstruction that correlates with simultaneous accumulation of interstitial macrophages and T lymphocytes expressing the respective surface receptors CCR2 and CCR5. The chemokine receptor-mediated leukocyte influx into the tubulointerstitium could offer a new potential target for therapeutic intervention in progressive renal tubulointerstitial fibrosis.

Animals↗

PubMed1997

A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1 alpha/LD78 alpha and chemotactic for T lymphocytes, but not for monocytes.

By searching the expressed sequence tag (EST) database, we identified partial cDNA sequences encoding a polypeptide with significant sequence identity to the human CC chemokine macrophage-inflammatory protein-1 alpha (MIP-1 alpha)/LD78 alpha. We determined the complete cDNA sequence that contained a reading frame of 89 amino acids with 61% identity to human MIP-1 alpha/LD78 alpha. The mRNA was expressed constitutively at high levels in human lung and at low levels in some lymphoid tissues. Furthermore, the mRNA was strongly induced in several human cell lines, including monocytic U937 cells, by PMA. From these results, we designated this novel CC chemokine as PARC from pulmonary and activation-regulated chemokine. In situ hybridization analyses showed that alveolar macrophages, follicular dendritic cells in the germinal centers of regional lymph nodes, and peripheral blood monocytes stimulated with LPS express PARC mRNA. Using the human CC chemokine yeast artificial chromosome contig that we constructed recently, we mapped the PARC gene (SCYA18) within one of the two subregions of the CC chemokine gene cluster at chromosome 17q11.2. To investigate its biologic activity, the PARC protein was expressed in insect cells. PARC was chemotactic for both activated (CD3+) T cells and nonactivated (CD14-) lymphocytes, but not for monocytes or granulocytes. Binding analysis using PARC fused with alkaline phosphatase-(His)6 showed the presence of a single class of receptors for PARC on lymphocytes with a Kd of 1.9 nM and 590 sites/cell. Thus, PARC is a novel CC chemokine with a close phylogenic relationship with MIP-1 alpha/LD78 alpha, but with a highly selective activity on lymphocytes.

Amino Acid Sequence↗

PubMed1997

Proinflammatory cytokines and Helicobacter pylori stimulate CC-chemokine expression in gastric epithelial cells.

Helicobacter pylori (H. pylori) has been shown to stimulate secretion of IL-8, a CXC-chemokine, from gastric epithelial cells, and this process is important in the induction of gastric mucosal inflammation associated with H. pylori infection. However, considering the biological effects and target cells, CC-chemokines may also be playing an important role in H. pylori-associated gastritis. In the present study, we investigated the expression of IL-8 (CXC-chemokine), MCP-1 (CC-chemokine), and RANTES (CC-chemokine) in human gastric mucosa by RT-PCR analysis. The positive rates of IL-8, MCP-1, and RANTES in 35 patients were 68.5%, 80%, and 80% respectively, suggesting the possible importance of CC-chemokines. We next examined the production of MCP-1 by MKN28 gastric epithelial cells. MKN28 cells were found to secrete MCP-1 in response to IL-1 beta or TNFalpha in a dose- and time-dependent manner. Quantitative RT-PCR analysis showed the induction of MCP-1 mRNA by these proinflammatory cytokines. Co-culture with H. pylori also induced the expression of MCP-1 mRNA. These results suggest that gastric epithelial cells secrete CC chemokine MCP-1 in response to proinflammatory cytokines and H. pylori, and this process may also be important in the chronic gastric inflammation associated with H. pylori infection.

Adult↗

PubMed1996

CC chemokines induce the generation of killer cells from CD56+ cells.

We describe here that members of the CC chemokines exhibit biological activities other than chemotaxis. Macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, monocyte chemoattractant protein-1 and RANTES, but not interleukin (IL)-8, induce the generation of cytolytic cells, designated here as CHAK (CC chemokine-activated killer) cells to distinguish them from IL-2-activated (LAK) cells. Like IL-2, CC chemokines can induce the proliferation and activation of killer cells. While incubating CC chemokines with CD4+ or CD8+ cells did not generate CHAK activity, all CC chemokines were capable of inducing CHAK activity upon incubating with CD56+ cells, suggesting that the primary effectors are NK cells. However, the presence of other cell types, such as CD4+ or CD8+, are necessary to induce the proliferation of CD56+ cells. Confirming the involvement of T cell-derived factors in inducing the proliferation of these cells, anti-IL-2 and anti-interferon-gamma, but not anti-IL-1 beta, anti-tumor necrosis factor-alpha, anti-IL-8, or anti-granulocyte/monocyte-colony-stimulating factor inhibited RANTES-induced proliferation of nylon wool column-nonadherent cells. Our results may have important clinical applications for the utilization of CHAK cells in the treatment of cancer and immunodeficient patients.

CD56 Antigen↗

PubMed2006

CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway.

Invasion of colorectal carcinomas (CC) is characterized by nuclear accumulation of beta-catenin, a key component of the Wnt pathway, in scattered tumor cells. beta-catenin acts in cooperation with T-cell factor (Tcf) HMG-box transcription factors as a transcriptional activator of genes involved in tumor progression. Overexpression of CD97, a molecule that correlates with dedifferentiation and tumor stage in CC, parallels to nuclear translocation of beta-catenin. Here, we investigated whether CD97 is a direct beta-catenin/Tcf target gene. SW480 CC cells were used to mimic the phenotypical switch between central and invasive tumor areas. We demonstrate two-fold higher CD97 expression and nuclear beta-catenin accumulation in cells grown at low density compared to cells cultured at high density, showing membrane-associated beta-catenin. This suggests that CD97 expression correlates with the cellular localization of beta-catenin. However, CD97 mRNA expression levels were not affected by Tcf-1 or Tcf-4 as determined in inducible dominant-negative (dn) Tcf CC cell lines. Furthermore, co-expression of wildtype (wt) or S33A mutated beta-catenin with Tcf-4 did not influence CD97 promoter activity. Inhibition of glycogen synthase kinase (GSK)-3beta, a negative regulator of the canonical Wnt pathway, had no influence on CD97 expression levels. In summary, enhanced CD97 expression in CC cells is regulated independent of beta-catenin/Tcf-4, and is thus not a direct target of the canonical Wnt pathway.

Antigens, CD↗