Expression of C–C chemokine TARC in human nasal mucosa and its regulation by cytokines

Terada, Nobuhisa; Nomura, Taishin; Kim, W. J.; Otsuka, Yuichiro; Takahashi, Riichi; Kishi, Hirohisa; Yamashita, Tetsuji; Sugawara, Naoto; Fukuda, Setsuya; Ikeda-Ito, T.; Konno, Akiyoshi

doi:10.1046/j.1365-2222.2001.01152.x

Cited by 68 publications

(67 citation statements)

References 29 publications

(29 reference statements)

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“…This swift induction appears to be typical, as similar kinetics are seen with many IL-4-induced genes including SOCS-1 [29,38], FIZZ1 [39], Eotaxin/CCL11 [28] and Eotaxin-3/CCL26 [27]. Most other cell types that were examined for IL-4 inducibility of TARC/CCL17 require simultaneous stimulation with TNF-a to up-regulate its expression [8,21,30,33,[40][41][42]. Such cooperative effects of IL-4 and TNF-a stimulation were shown before for other genes.…”

Section: Ccl17 In T Cells and To Characterize The Regulatory Promotermentioning

confidence: 77%

“…Hence, the present work was intended to study the IL-4 inducibility of the expression of TARC/ [27]. Most other cell types that were examined for IL-4 inducibility of TARC/CCL17 require simultaneous stimulation with TNF-a to up-regulate its expression [8,21,30,33,[40][41][42]. Such cooperative effects of IL-4 and TNF-a stimulation were shown before for other genes.…”

mentioning

confidence: 73%

“…TARC/CCL17-mediated recruitment of Th2 cells and CLA + CD4 + T cells was shown to play a major role in allergic diseases like atopic dermatitis [16,17], allergic asthma [18][19][20], allergic rhinitis [21] and allergic contact dermatitis [22].…”

Section: Introductionmentioning

confidence: 99%

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IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites

et al. 2006

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A cardinal feature of allergic disorders and immune responses is enhanced leukocyte trafficking. This is largely orchestrated by chemokines. The CC chemokine thymus-and activation-regulated chemokine (TARC/CCL17) selectively attracts Th2 cells via the G protein-coupled chemokine receptor CCR4. We show here that TARC/CCL17 is expressed by human T cells upon stimulation with IL-4. Mapping of the transcriptional start site revealed the presence of two putative STAT6 binding motifs in proximity to the start position. EMSA and chromatin immunoprecipitation experiments demonstrated that STAT6 was able to bind to both motifs. A fragment of the TARC/CCL17 promoter containing both sites was tested in reporter gene assays for IL-4 inducibility. The promoter was inducible in a STAT6-deficient cell line only after introduction of functional STAT6. When mutations were inserted into one of the STAT6 motifs, IL-4-induced promoter activation was reduced. With both sites mutated, inducibility was completely abrogated. These data demonstrate collectively that T cells serve as a source of TARC/CCL17 when stimulated with IL-4 and that STAT6 is essential for this. IntroductionChemokines are structurally related 8-12-kDa chemoattractant cytokines that regulate leukocyte trafficking and inflammatory diseases. Depending on the motif displayed by the first or first two of their conserved cysteines, they have been classified into C, CC, CXC or CX3C chemokine subfamilies. Chemokines have been shown to not only regulate hemopoietic cell migration but also to be involved in a number of other physiological and pathological processes [1]. The 8-kDa thymus-and activation-regulated chemokine (TARC/CCL17) was first isolated from phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMC) by Imai et al. in 1996 [2] by means of a signal sequence trap method [3]. The TARC/CCL17 gene is located on chromosome 16q13 in a cluster with MDC/ CCL22 and Fractalkine/CX3CL1 [4]. It encodes a highly basic 94 amino acid residues long preprotein with a cleavage site between Ala23 and Ala24. The mature TARC/CCL17 protein is 71 amino acid residues in length and was shown to be constitutively expressed in thymus [2] and, upon activation with different inducers, in several cell types including PBMC [5], monocytes [6], dendritic cells [7], endothelial cells, and bronchial epithelial cells [8].Leukocytes are activated by chemokines through seven-transmembrane G protein-coupled receptors. Based on the subfamily of chemokines they bind, chemokine receptors are named XCR1, CCR1-9, CXCR1-5 and CX3CR1 [9]. The specific functional high-affinity receptor for TARC/CCL17 is the CC chemokine receptor 4 (CCR4), which has also been shown to serve as receptor for CCL22/MDC (macrophage-derived chemokine). CCR4 is predominantly Interleukin-4 (IL-4), mainly produced by Th2 T cells, mast cells, basophils and eosinophils, appears to be a crucial factor in allergic responses. IL-4 induces differentiation of allergen-specific Th2 cells and class switching towards IgE produc...

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Section: Ccl17 In T Cells and To Characterize The Regulatory Promotermentioning

confidence: 77%

mentioning

confidence: 73%

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IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites

et al. 2006

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“…Airway epithelial cells induce migration of Th1 cells into mucosae via production of the CXCR3 ligands, CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC), and induce migration of Th2 cells via production of the CCR8 ligand CCL1 (I-309) and the CCR4 ligands CCL17 (TARC) and CCL22 (MDC) (Figure 1) [42][43][44][45][46][47]. CXCR3 is expressed on activated T cells, predominantly of the Th1 phenotype, as well as on NK cells and a subset of circulating memory CD4 + and CD8 + T cells.…”

Section: Interaction Of Epithelial Cells With T Cellsmentioning

confidence: 99%

Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity

Kato

Schleimer

2007

Current Opinion in Immunology

293

254

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“…Thus, the expressions of IL-4, CCR4, and CCR8 may require allergen stimulation in the inflamed region. In addition, TARC and MDC are expressed not only in airway epithelium but also in the other organs such as skin (31,32) and the nose (33). Taken together, it is suggested that T cells in the peripheral blood, especially Th2-type cells, of asthmatic patients migrate from blood into bronchial tissue without inflammatory stimulation by a mechanism other than chemokines such as MDC and TARC and their ligands of CCR4.…”

Section: Discussionmentioning

confidence: 99%

T Cells of Atopic Asthmatics Preferentially Infiltrate Into Human Bronchial Xenografts in SCID Mice

Tsumori

Kohrogi

Goto

et al. 2003

The Journal of Immunology

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T cells play an important role in the pathogenesis of bronchial asthma. However, it is not completely known how circulating lymphocytes infiltrate into the airways of asthmatic patients. Because SCID mice are unable to reject xenogenic transplants, many xenotransplant models using various human tissues have been developed. Therefore, to examine the interaction between bronchi and T lymphocytes of asthma, it may be possible to use the human bronchial xenograft and PBMC xenograft in SCID mice. We transplanted human bronchi into the subcutaneum of SCID mice and i.p. injected PBMCs that were obtained from patients with atopic asthma, atopic dermatitis and rheumatoid arthritis, and normal subjects (asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice). There was no difference in the percentage of CD3-, CD4-, CD8-, CD25-, CD45RO-, CD103-, and cutaneous lymphocyte Ag-positive cells in PBMCs among the patients with asthma, dermatitis, rheumatoid arthritis, and normal subjects, and CD3-positive cells in peripheral blood of asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice. The number of CD3-, CD4-, and CD8-positive cells in the xenografts of asthmatic huPBMC-SCID mice was higher than those of dermatitis, rheumatic, and normal huPBMC-SCID mice. IL-4 mRNA and IL-5 mRNA were significantly higher in the xenografts of asthmatic huPBMC-SCID mice than those in the xenografts of normal huPBMC-SCID mice, but there were no significant differences in the expressions of IL-2 mRNA or IFN-γ mRNA between them. These findings suggest that T cells, especially Th2-type T cells, of asthmatics preferentially infiltrate into the human bronchi.

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Expression of C–C chemokine TARC in human nasal mucosa and its regulation by cytokines

Abstract: These results demonstrate a crucial role of nasal epithelial cells in the expression of TARC, and that Th2 cytokine IL-4 and IL-13 may promote Th2 responses by inducing TARC production from epithelial cells.

Cited by 68 publications

References 29 publications

IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites

IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites

Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity

T Cells of Atopic Asthmatics Preferentially Infiltrate Into Human Bronchial Xenografts in SCID Mice

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