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IFN--Primed Macrophages Exhibit Increased CCR2-Dependent Migration and Altered IFN- Responses Mediated by Stat1¹

Xiaoyu Hu^*, Kyung-Hyun Park-Min, Hao H. Ho^* and Lionel B. Ivashkiv^2,*,

^* Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, and Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021

Priming of macrophages with IFN- increases cellular responsiveness to inflammatory stimuli, including IFN- itself. We described previously that priming with subactivating concentrations of IFN- increased Stat1 expression and resulted in enhanced activation of Stat1 and of a subset of IFN--responsive genes when primed macrophages were restimulated with low doses of IFN-. In this study, we determined the effects of IFN- priming on the macrophage transcriptome and on transcriptional responses to high saturating concentrations of IFN-. At baseline, primed macrophages expressed a small subset of IFN--inducible genes, including CCR2, and exhibited increased migration in response to CCL2. Activation of gene expression by high concentrations of IFN- was altered in primed macrophages, such that activation of a subset of IFN--inducible genes was attenuated. A majority of genes in this "less induced" category corresponded to genes that are induced by IFN- 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--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- induction of certain tissue-destructive genes.

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