title: CCL18/PARC stimulates hematopoiesis in long-term bone marrow cultures indirectly through its effect on monocytes.
abstract: 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 colony-promoting 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.
authors.affiliation: Division of Cancer Biology, Ste 100, La Jolla Institute for Molecular Medicine, 4570 Executive Dr, San Diego, CA 92121, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Wimmer
authors.forename: Sophia K
authors.initials: SK
authors.lastname: Khaldoyanidi
authors.forename: Martin
authors.initials: M
authors.lastname: Judex
authors.forename: Naira
authors.initials: N
authors.lastname: Serobyan
authors.forename: Richard G
authors.initials: RG
authors.lastname: Discipio
authors.forename: Ingrid U
authors.initials: IU
authors.lastname: Schraufstatter
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001853:Bone Marrow / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000378:metabolism* / Q000494:pharmacology; D003114:Colony-Forming Units Assay / Q000379:methods; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: C111792:CCL18 protein, human; D019742:Chemokines, CC; D017077:Culture Media, Conditioned; D016207:Cytokines