Regulation of Granulocyte and Macrophage Populations of Murine Bone Marrow Cells by G-CSF and CD137 Protein

Abstract

BackgroundGranulocytes and monocytes/macrophages differentiate from common myeloid progenitor cells. Granulocyte colony-stimulating factor (G-CSF) and CD137 (4-1BB, TNFRSF9) are growth and differentiation factors that induce granulocyte and macrophage survival and differentiation, respectively. This study describes the influence of G-CSF and recombinant CD137-Fc protein on myelopoiesis.Methodology/Principal FindingsBoth, G-CSF and CD137 protein support proliferation and survival of murine bone marrow cells. G-CSF enhances granulocyte numbers while CD137 protein enhances macrophage numbers. Both growth factors together give rise to more cells than each factor alone. Titration of G-CSF and CD137 protein dose-dependently changes the granulocyte/macrophage ratio in bone marrow cells. Both factors individually induce proliferation of hematopoietic progenitor cells (lin-, c-kit+) and differentiation to granulocytes and macrophages, respectively. The combination of G-CSF and CD137 protein further increases proliferation, and results in a higher number of macrophages than CD137 protein alone, and a lower number of granulocytes than G-CSF alone demonstrating that CD137 protein-induced monocytic differentiation is dominant over G-CSF-induced granulocytic differentiation. CD137 protein induces monocytic differentiation even in early hematopoietic progenitor cells, the common myeloid progenitors and the granulocyte macrophage progenitors.Conclusions/SignificanceThis study confirms earlier data on the regulation of myelopoiesis by CD137 receptor - ligand interaction, and extends them by demonstrating the restriction of this growth promoting influence to the monocytic lineage.

Targeting CD137 enhances the efficacy of cetuximab

“…In further support by the Winn assay (47), we observed that anti-CD137 mAb following cetuximab treatment enhanced adaptive immunity with a significantly higher rate of CD8 + T cell-mediated protection to EGFR-expressing and nonexpressing tumors. The role of adaptive immunity and CD8 + T cells may be an on-target effect of anti-CD137 mAbs in vivo influencing the function of multiple cell types including hematopoietic cells such as granulocytes, T cells, B cells, DCs, and monocytes in addition to NK cells, as well as nonhematopoietic cells (31,(48)(49)(50)(51). Recently, Lee et al reported that tumor-targeting mAbs such as cetuximab induce an adaptive tumor antigen-specific T cell response that is primed by NK cell activation and subsequent NK cell-DC crosstalk (20).…”

Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer

“…The nu/nu and SCID mice are both competent in NK cells and macrophages and complement but lack a functional adaptive immune response. However, mAbs targeting CD137 in vivo likely influence the function of multiple cell types, including hematopoietic cells such as granulocytes, T cells, B cells, dendritic cells, and monocytes, in addition to NK cells, as well as nonhematopoietic cells (25,(40)(41)(42)(43). In particular, our partially immunodeficient mouse models do not explore the impact of trastuzumab and anti-CD137 combination therapy on the adaptive immune response.…”

Comparative Analysis of Monocyte Subsets in the Pig

“…Selective expression of G-CSF (CSF3) receptor was also shared by pig and human CD14 hi monocytes. CSF3 controls the production, differentiation, and function of granulocytes (34), and has also been described as a maturation factor for monocytes (35,36). Production of CD14 hi monocyte subset in the bone marrow may be coordinated with granulocytes (15,37).…”