Differential sensitivity of mouse mononuclear phagocytes to CSF-1 and LPS: the potential in vivo relevance of enhanced IL-6 gene expression

In this report, we compared the responsiveness of subpopulations of mononuclear phagocytes (MNP) to the actions of the monocyte-macrophage colony-stimulating factor (CSF-1) and lipopolysaccharide (LPS), as measured by the expression of the IL-6 (Il6) gene. It was seen that neither monocytes nor elicited peritoneal macrophages (PMphi) responded directly to CSF-1 compared with resident PMphi that were induced to express high levels of Il6 mRNA and release IL-6 protein. Resident PMphi released basal (constitutive) amounts of IL-6, while constitutive release by monocytes and elicited PMphi was barely detectable. Monocytes and elicited PMphi expressed similar levels of sensitivity to LPS, as measured by IL-6 release, and were less reactive than resident PMphi. When CSF-1 and LPS were added simultaneously to resident PMphi, a dose-dependent synergistic release of IL-6 was seen. Elicited PMphi also responded synergistically but required higher levels of CSF-1 and LPS, while monocytes failed to respond synergistically under any conditions. A similar synergistic effect was also seen in vivo when mice were injected with CSF-1 and LPS. Under these conditions, only resident peritoneal cells were shown to release IL-6 ex vivo while blood leukocytes and spleen cells released minimal amounts. These findings indicate that the stage of differentiation/maturation of MNP may be important for the ability of CSF-1 to render the cells sensitive to secondary stimulation, such as by LPS, and determines to what extent MNP subpopulations contribute to inflammatory responses in vivo.