Submitted April 3, 2006
Accepted July 13, 2006
CCL18/PARC stimulates hematopoiesis in long-term bone-marrow cultures indirectly through its effect on monocytes
Antonia Wimmer, Sophia K. Khaldoyanidi, Martin Judex, Naira Serobyan, Richard G. DiScipio, and Ingrid U. Schraufstatter*
La Jolla Institute for Molecular Medicine, San Diego, CA, USA
Sidney Kimmel Cancer Center, La Jolla, CA, USA
* Corresponding author; email: ingrid{at}ljimm.org.
Chemokines play a role in regulation of hematopoietic stem cell functions including migration, proliferation and retention. Here, the involvement of CCL18 in regulation of bone marrow hematopoiesis was investigated. The treatment of human long-term bone marrow cultures (LTBMC) with CCL18 resulted in a significant stimulation of hematopoiesis, as measured by the total number of hematopoietic cells and their committed progenitors produced in cultures. Monocytes/macrophages, which showed almost double the survival in the presence of CCL18 compared to controls, were the primary cells mediating this effect. Conditioned media from CCL18-treated mature monocytes contained colony-promoting activity that increased the number of colonies formed by hematopoietic progenitor cells. Gene expression profiling of CCL18-stimulated monocytes demonstrated >200 differentially expressed genes including those regulating apoptosis (caspase 8), and proliferation (IL-6, IL-15 and 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 which significantly inhibited colony-promoting activity of CCL18-stimulated conditioned medium. In addition to the effect on monocytes, CCL18 also facilitated the formation of the adherent layer in LTBMC, and increased proliferation of stromal fibroblast-like cells.
