IFN-γ-Primed Macrophages Exhibit Increased CCR2-Dependent Migration and Altered IFN-γ Responses Mediated by Stat1

Abstract

Priming of macrophages with IFN-γ increases cellular responsiveness to inflammatory stimuli, including IFN-γ itself. We described previously that priming with subactivating concentrations of IFN-γ increased Stat1 expression and resulted in enhanced activation of Stat1 and of a subset of IFN-γ-responsive genes when primed macrophages were restimulated with low doses of IFN-γ. In this study, we determined the effects of IFN-γ priming on the macrophage transcriptome and on transcriptional responses to high saturating concentrations of IFN-γ. At baseline, primed macrophages expressed a small subset of IFN-γ-inducible genes, including CCR2, and exhibited increased migration in response to CCL2. Activation of gene expression by high concentrations of IFN-γ was altered in primed macrophages, such that activation of a subset of IFN-γ-inducible genes was attenuated. A majority of genes in this “less induced” category corresponded to genes that are induced by IFN-γ via Stat1-independent but Stat3-dependent pathways and have been implicated in inflammatory tissue destruction. One mechanism of attenuation of gene expression was down-regulation of Stat3 function by increased levels of Stat1. These results reveal that priming enhances migration to inflammatory chemokines and identify IFN-γ-inducible genes whose expression is attenuated by high levels of Stat1. The increase in Stat1 expression during priming provides a mechanism by which physiological regulation of the relative abundance of Stat1 and Stat3 impacts on gene expression. Our results also suggest that, in addition to inducing hypersensitivity to inflammatory stimuli, IFN priming delivers a homeostatic signal by attenuating IFN-γ induction of certain tissue-destructive genes.

Long-acting progestin-only contraceptives impair endometrial vasculature by inhibiting uterine vascular smooth muscle cell survival

“…In support of this mechanism, the STAT1 inhibitor, MTA, abolishes proliferative effects of CCL2 on progestin-treated VSMCs. These observations are consistent with reports that: (i) the CCL2 receptor CCR2 is present in human and rat VSMCs (30,31), (ii) STAT1 signaling induces VSMC proliferation (32), and (iii) CCR2 activates STAT1 signaling (33).…”

IFN-γ does not mimic the catabolic effects of TNF-α

“…The present study demonstrates that IFN-␥ stimulates early receptor signaling, as evidenced by the phosphorylation of Stat1, a transcriptional regulatory protein linked to IFN-␥ membrane receptors (18). However, IFN-␥ failed to elicit an increase in oxidant activity within C2C12 myotubes.…”

“…Fig. 1, as a positive indicator for IFN-␥ signaling, we measured the phosphorylation of Stat1 since this early postreceptor signaling element appears to be critical for IFN-␥ responsiveness (18). Myotubes were treated with IFN-␥ for up to 60 min.…”

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…8,69 The inhibition of CCR2 expression by pro-inflammatory agents such as IFN-c has been proposed to retain Mws at sites of inflammation and to act as a negative feedback loop for monocyte recruitment from the blood. 70 However, because the number of uterine Mws remains relatively constant throughout gestation, circulating blood monocytes are expected to be continuously recruited to the decidua by both stromal and trophoblast cells in response to diverse chemotactic factors. 8,69 Moreover, Mws are expected to be motile within both the decidua and the fetal membranes, as they express higher levels of genes that promote the activation of migration.…”