Interferon-γ Increases Expression of Chemokine Receptors CCR1, CCR3, and CCR5, But Not CXCR4 in Monocytoid U937 Cells
Davide ZellaOxana BarabitskajaJennifer M. BurnsFabio RomerioDaniel E. DunnMaria Grazia RevelloGiuseppe GernaMarvin S. ReitzRobert C. GalloFrank Weichold
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CCR1
CCR3
Chemokine receptor CCR5
CCL13
CCL21
CC chemokine receptors
CXC chemokine receptors
CXCL2
XCL2
CCR1
CCR3
Macrophage inflammatory protein
Chemokine receptor CCR5
CCR2
CCL13
CCL3
CXCL2
CCL21
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CCL22
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Signals via chemokine receptors play an important role in the accumulation of eosinophils at allergic inflammatory sites. Eosinophils constitutively express CC chemokine receptor 3 (CCR3) and, to a lesser extent, CCR1. CCR3 is mainly responsible for migration of resting eosinophils, and its specific ligand, eotaxin, represents the most potent chemoattractant for eosinophils. Some reports also suggest the expression of CXC chemokine receptor 1 (CXCR1) and/or CXCR2 in eosinophils. In addition, we recently reported the functional expression of CXCR4. The ligand of CXCR4, stromal cell-derived factor-1 (SDF-1), was able to induce a strong migratory response comparable to that by eotaxin. In contrast to the CCR3/eotaxin system which is mainly regulated at the level of ligand production, the CXCR4/SDF-1 system is regulated at the level of receptor expression. CXCR4 expression was completely attenuated by IL-4 and IL-5 and upregulated by IFN-gamma and dexamethasone, while CCR3 expression was only marginally affected. The balance between the biological effects of these chemokine systems may affect the distribution and migration of eosinophils.
CXC chemokine receptors
CCL13
CCR3
CCL21
CXCL2
CC chemokine receptors
XCL2
CCR1
CCL25
Chemokine receptor CCR5
CCL17
CXCL5
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T helper cells type 1 (Th1s) that produce interferon-γ predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory conditions, whereas Th2s which produce large amounts of IL-4 and IL-5 upregulate IgE production and are prominent in the pathogenesis of allergic diseases. The precise factors determining whether Th1- or Th2-mediated immune responses preferentially occur at a peripheral site of antigen exposure are largely unknown. Chemokines, a superfamily of polypeptide mediators, are a key component of the leukocyte recruitment process. Here we report that among four CXC (CXCR1-4) and five CC (CCR1-5) chemokine receptors analyzed, CXCR3 and CCR5 are preferentially expressed in human Th1s. In contrast, Th2s preferentially express CCR4 and, to a lesser extent, CCR3. In agreement with the differential chemokine receptor expression, Th1s and Th2s selectively migrate in response to the corresponding chemokines. The differential expression of chemokine receptors may dictate, to a large extent, the migration and tissue homing of Th1s and Th2s. It may also determine different susceptibility of Th1s and Th2s to human immunodeficiency virus strains using different fusion coreceptors.
CCL13
CCR1
CXC chemokine receptors
CXCR3
CCR3
CXCL2
CCL7
CXCL16
Chemokine receptor CCR5
XCL2
CCL21
CC chemokine receptors
CX3CL1
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CXC chemokine receptors
CCL21
CCR3
CCR1
Chemokine receptor CCR5
CXCL2
CC chemokine receptors
CCL13
XCL2
CCL7
CXCL14
CCR2
CXCL16
CCL17
CCL22
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Chemokine and chemokine receptor interactions may have important roles in leukocyte migration to specific immune reaction sites. Recently, it has been reported that CXC chemokine receptor (CXCR) 3 and CC chemokine receptor (CCR) 5 were preferentially expressed on T(h)1 cells, and CCR3 and CCR4 were preferentially expressed on T(h)2 cells. To investigate chemokine receptor expression by T(h) subsets in vivo, we analyzed cytokine (IL-2, IL-4 and IFN-gamma) and chemokine receptor (CXCR3, CXCR4, CCR3, CCR4 and CCR5) mRNA expression by individual peripheral CD4(+) memory T cells after short-term stimulation, employing a single-cell RT-PCR method. This ex vivo analysis shows that the frequencies of cells expressing chemokine receptor mRNA were not significantly different between T(h)1 and T(h)2 cells in normal peripheral blood. To assess a potential role of in vivo stimulation, we also analyzed unstimulated rheumatoid arthritis synovial CD4(+) memory T cells. CXCR3, CXCR4, CCR3 and CCR5 expression was detected by individual synovial T cells, but the frequencies of chemokine receptor mRNA were not clearly different between T(h)1 and non-T(h)1 cells defined by expression of IFN-gamma or lymphotoxin-alpha mRNA in all RA patients. These data suggest that chemokine receptor expression does not identify individual memory T cells producing T(h)-defining cytokines and therefore chemokine receptor expression cannot be a marker for T(h)1 or T(h)2 cells in vivo.
CCL13
CCL21
CCL17
CXCL16
XCL2
CC chemokine receptors
Chemokine receptor CCR5
CXCR3
CXCL2
CCL5
CXC chemokine receptors
CCR1
CCR4
CCR2
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Citations (73)
CXC chemokine receptors
CCL21
CCR1
CCR3
CC chemokine receptors
CXCL2
Chemokine receptor CCR5
CCL13
XCL2
CCL7
CXCL14
CXCL16
CCR2
CCL17
CCL22
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Citations (128)
CCR1
CCR3
CC chemokine receptors
XCL2
CCL21
CCL13
Chemokine receptor CCR5
CCL3
CCR2
CCL7
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CCR1
Chemokine receptor CCR5
CCL13
CCR3
CCL21
CC chemokine receptors
CXC chemokine receptors
CXCL2
XCL2
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Chemokines and their receptors are important elements for the selective attraction of various subsets of leukocytes. To better understand the selective migration of functional subsets of T cells, chemokine receptor expression was analyzed using monoclonal antibodies, RNase protection assays, and the response to distinct chemokines. Naive T cells expressed only CXC chemokine receptor (CXCR)4, whereas the majority of memory/activated T cells expressed CXCR3, and a small proportion expressed CC chemokine receptor (CCR)3 and CCR5. When polarized T cell lines were analyzed, CXCR3 was found to be expressed at high levels on T helper cell (Th)0s and Th1s and at low levels on Th2s. In contrast, CCR3 and CCR4 were found on Th2s. This was confirmed by functional responses: only Th2s responded with an increase in [Ca2+]i to the CCR3 and CCR4 agonists eotaxin and thymus and activation regulated chemokine (TARC), whereas only Th0s and Th1s responded to low concentrations of the CXCR3 agonists IFN-γ–inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig). Although CCR5 was expressed on both Th1 and Th2 lines, it was absent in several Th2 clones and its expression was markedly influenced by interleukin 2. Chemokine receptor expression and association with Th1 and Th2 phenotypes was affected by other cytokines present during polarization. Transforming growth factor β inhibited CCR3, but enhanced CCR4 and CCR7 expression, whereas interferon α inhibited CCR3 but upregulated CXCR3 and CCR1. These results demonstrate that chemokine receptors are markers of naive and polarized T cell subsets and suggest that flexible programs of chemokine receptor gene expression may control tissue-specific migration of effector T cells.
XCL2
CCL13
CC chemokine receptors
CXCR3
CCR3
Chemokine receptor CCR5
CCL21
CCR4
CCL17
CXC chemokine receptors
CXCL16
CCL22
CCR1
CCL20
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CXC chemokine receptors
CCL13
CX3CR1
CCR1
CCR3
CCR10
CXCL2
CCL21
CC chemokine receptors
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XCL2
CX3CL1
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