Modification of macrophage differentiation: Dimethylnitrosamine induced alteration in the responses towards the regulatory signals controlling myelopoiesis

Abstract

Results from our laboratory have demonstrated that the alteration in cellular immunity (CMI) resulting from exposure to dimethylnitrosamine (DMN) in vivo is due to changes in myelopoiesis. Bone marrow stem cells showed no alterations in their capacity to generate CFU-S (pleuripotent stem cells) nor were there any changes in the number of CFU-Mix colonies (IL-3 responsive stem cells) arising from the bone marrow of DMN exposed mice. However, the generation of G/M-CSF and CSF-1 responsive colonies (CFU-G/M and CFU-M) were altered, resulting in an increase in the number of colonies. G/M-CSF colonies generated from the bone marrow stem cells obtained from DMN exposed mice also had increased numbers of cells produced by each colony (total cells/CFU). Indirect immunofluorescence studies demonstrated no changes in the granulocyte/macrophage subsets following G/M-CSF stimulation of bone marrow stem cells obtained from DMN exposed mice. However, there was no change in the total number of cells generated by CSF-1 from the marrows of DMN exposed mice as compared to vehicle treated mice. Marrow cells from DMN exposed mice cultured in vitro with G/M-CSF showed both a shift in their peak proliferative response from 48–72 h to 30–60 h and an increased proliferative response. These same marrow cells showed no shift in their kinetics but a decrease in their proliferative response to CSF-1. Examination of the sera from DMN exposed mice for alterations in the regulatory factors controlling myelopoiesis demonstrated a net decrease of CSF-1 activity but no changes in the concentrations of two inhibitory factors, transferrin and lactoferrin. These results indicate DMN exposure is affecting macrophage myelopoiesis at the level of the G/M-CSF and CSF-1 responsive cells through: (1) alterations in the responsiveness of these cells to the growth factor(s) and (2) changes in serum borne regulatory factors controlling myelopoiesis.