Chemokine PARC Gene (SCYA18) Generated by Fusion of Two MIP-1α/LD78α-like Genes

Tasaki, Yukino; Fukuda, Sachiyo; M, Iio; Miura, Retsu; Imai, Toshio; Sugano, Sumio; Yoshie, Osamu; Hughes, Austin L.; Nomiyama, Hisayuki

doi:10.1006/geno.1998.5670

Cited by 44 publications

(40 citation statements)

References 10 publications

(15 reference statements)

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“…CCL18 has not been found in the murine genome, and the human gene has supposedly evolved from duplication of the MIP-1␣ gene 34,35 and thus far has been detected only in humans and monkeys. 5 We found that the total number of mature hematopoietic cells and their progenitors produced in CCL18-treated LTBMCs was increased compared with control (nontreated or heat-inactivated CCL18).…”

Section: Discussionmentioning

confidence: 99%

CCL18/PARC stimulates hematopoiesis in long-term bone marrow cultures indirectly through its effect on monocytes

Wimmer

Khaldoyanidi

Judex

et al. 2006

Blood

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Chemokines play a role in regulating hematopoietic stem cell function, including migration, proliferation, and retention. We investigated the involvement of CCL18 in the regulation of bone marrow hematopoiesis. Treatment of human long-term bone marrow cultures (LTBMCs) with CCL18 resulted in significant stimulation of hematopoiesis, as measured by the total number of hematopoietic cells and their committed progenitors produced in culture. Monocytes/macrophages, whose survival was almost doubled in the presence of CCL18 compared with controls, were the primary cells mediating this effect. Conditioned media from CCL18-treated mature monocytes fostered colony-promoting activity that increased the number of colonies formed by hematopoietic progenitor cells. Gene expression profiling of CCL18-stimulated monocytes demonstrated more than 200 differentially expressed genes, including those regulating apoptosis (caspase-8) and proliferation (IL-6, IL-15, stem cell factor [SCF]). Up-regulation of these cytokines was confirmed on the protein expression level. The contribution of SCF and IL-6 in CCL18-mediated stimulatory activity for hematopoiesis was confirmed by SCF-and IL-6-blocking antibodies that significantly inhibited the colonypromoting activity of CCL18-stimulated conditioned medium. In addition to the effect on monocytes, CCL18 facilitated the formation of the adherent layer in LTBMCs and increased the proliferation of stromal fibroblast-like cells. IntroductionPulmonary and activation-regulated chemokine (CCL18/PARC) 1 -also referred to as DC-CK-1, 2 AMAC-1, and MIP-4-is a member of the CC-chemokine family most closely related to MIP-1␣ and with which it shares 61% sequence identity. However, it does not activate the same receptors as does MIP-1␣, which is a ligand for both CCR1 and CCR5. Thus far, the identity of the CCL18 receptor has not been elucidated, though CCL18 is a noncompetitive inhibitor for CCL11/eotaxin binding to the CCR3. 3 In spite of various reports suggesting a role for CCL18 in various chronic, primarily T H 2-mediated diseases, 4-8 assessing its function experimentally has been difficult because it appears to be present in primates only, obviating small animal models.In vitro findings show that CCL18 is chemotactic for lymphocytes, 1 particularly naive T cells 2 and B cells, 9 and for immature dendritic cells. 10 Although freshly isolated monocytes do not respond to CCL18, maturing monocytes/macrophages cultured for 2 to 4 days acquire transient responsiveness to CCL18. 11 More unusually for a chemokine, CCL18 activates fibroblasts, leading to increased proliferation and collagen production by these cells. 12 CCL18 is produced by a number of leukocytes. It has been detected in high concentrations in the lung, especially in alveolar macrophages, 1 and in lower concentrations in various lymphatic tissues, 1 dendritic cells, 2 adherent monocytes, and eosinophils. 11 Although CCL18 expression has been demonstrated in bone marrow, 1,11 the role of CCL18 in the regulation of bone marrow hematopoi...

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Section: Discussionmentioning

confidence: 99%

CCL18/PARC stimulates hematopoiesis in long-term bone marrow cultures indirectly through its effect on monocytes

Wimmer

Khaldoyanidi

Judex

et al. 2006

Blood

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“…Therefore, CCL18 production by immature DC could be part of a default strategy to limit the uncontrolled generation of inflammatory reactions. Unfortunately, CCL18 was generated by the fusion of two macrophage inflammatory protein-1␣-like genes, an event that happened late in evolution (32,33). No rodent CCL18 exists, and this makes it impossible to test this hypothesis in an in vivo experimental model.…”

Section: Discussionmentioning

confidence: 99%

Unique Regulation of CCL18 Production by Maturing Dendritic Cells

Vulcano

Struyf

Scapini

et al. 2003

The Journal of Immunology

137

113

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Dendritic cells (DC) orchestrate the trafficking of lymphocytes by secreting chemokines with different specificity and function. Chemokines are produced at higher levels by mature DC. This study shows that CCL18 is one of the most abundant chemokines produced by immature DC. In contrast to all other chemokines investigated to date, CCL18 was selectively down-regulated during the maturation process induced by LPS, TNF, CD40 ligand, Staphylococcus aureus Cowan I, Candida albicans, and influenza virus. IL-10 and vitamin D3, two known inhibitors of DC differentiation and function, strongly promoted CCL18 secretion, whereas IFN-γ, a costimulator of DC function, inhibited its production. IL-10 also induced CCL18 secretion in blood myeloid DC. No CCL18 secretion was observed in blood plasmacytoid DC. The opposite pattern of regulation was observed for CCL20, a prototypic inflammatory chemokine. CCL18 was found to be a chemotactic factor for immature DC. Therefore, CCL18 may act as a chemotactic signal that promotes the colocalization of immature DC with naive T lymphocytes in an IL-10-dominated environment with the consequent generation of T regulatory cells. These characteristics suggest that CCL18 may be part of an inhibitory pathway devoted to limiting the generation of specific immune responses at peripheral sites.

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“…CCL18 is also dysregulated in a number of other diseases without preferential Th2 polarization, such as leukemia and Gaucher disease. 16,17 It is of interest that the CCL18 gene is thought to be absent in rodents 18 and is still an orphan chemokine without known receptor, precluding experimental studies to assess its functionality in vivo.…”

Section: Introductionmentioning

confidence: 99%

CCL18 differentiates dendritic cells in tolerogenic cells able to prime regulatory T cells in healthy subjects

Azzaoui

Yahia

Chang

et al. 2011

Blood

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The aim of this study was to evaluate the nonchemotactic function of CCL18 on human dendritic cells (DCs). In different protocols of DC differentiation, CCL18 was highly produced, suggesting that it may constitute a mandatory mediator of the differentiation process. Differentiation of monocytes from healthy subjects in the presence of granulocyte-macrophage colony-stimulating factor and CCL18 led to the development of DCs with a semimature phenotype, with intermediate levels of costimulatory and MHC class II molecules, increased CCR7 expression, which induced, in coculture with allogenic naive T cells, an increase in IL-10 production. The generated T cells were able to suppress the proliferation of effector CD4 ؉ CD25 ؊ cells, through a cytokine-dependent mechanism, and exhibited characteristics of type 1 T regulatory cells. The generation of tolerogenic DCs by CCL18 was dependent on the production of indoleamine 2,3-dioxigenase through an interleukin-10-mediated mechanism. Surprisingly, when DCs originated from allergic patients, the tolerogenic effect of CCL18 was lost in relation with a decreased binding of CCL18 to its putative receptor. This study is the first to define a chemokine able to generate tolerogenic DCs. However, this function was absent in allergic donors and may participate to the decreased tolerance observed in allergic diseases. (Blood. 2011;118(13): 3549-3558)

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Chemokine PARC Gene (SCYA18) Generated by Fusion of Two MIP-1α/LD78α-like Genes

Cited by 44 publications

References 10 publications

CCL18/PARC stimulates hematopoiesis in long-term bone marrow cultures indirectly through its effect on monocytes

CCL18/PARC stimulates hematopoiesis in long-term bone marrow cultures indirectly through its effect on monocytes

Unique Regulation of CCL18 Production by Maturing Dendritic Cells

CCL18 differentiates dendritic cells in tolerogenic cells able to prime regulatory T cells in healthy subjects

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