Signal Integration and Transcriptional Regulation of the Inflammatory Response Mediated by the GM-/M-CSF Signaling Axis in Human Monocytes

Abstract

Summary: In recent years, the macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage CSF (GM-CSF) cytokines have been identified as opposing regulators of the inflammatory program. However, the two cytokines are simultaneously present in the inflammatory milieu, and it is not clear how cells integrate these signals. In order to understand the regulatory networks associated with the GM/M-CSF signaling axis, we analyzed DNA methylation in human monocytes. Our results indicate that GM-CSF induces activation of the inflammatory program and extensive DNA methylation changes, while M-CSF-polarized cells are in a less differentiated state. This inflammatory program is mediated via JAK2 associated with the GM-CSF receptor and the downstream extracellular signal-regulated (ERK) signaling. However, PI3K signaling is associated with a negative regulatory loop of the inflammatory program and M-CSF autocrine signaling in GM-CSF-polarized monocytes. Our findings describe the regulatory networks associated with the GM/M-CSF signaling axis and how they contribute to the establishment of the inflammatory program associated with monocyte activation. : Rodriguez et al. show that GM-CSF and M-CSF give rise to opposing phenotypes in the context of inflammation. Inflammation induced by GM-CSF is mediated by JAK2 and the downstream MAPK signaling pathway. However, PI3K signaling is associated with a negative regulatory loop of this program and the stimulation of autocrine production of M-CSF. Keywords: epigenetics, GM-CSF, M-CSF, DNA methylation, chromatin, monocyte, macrophage, polarization, differentiation, plasticity