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Stat4 Is Expressed in Activated Peripheral Blood Monocytes, Dendritic Cells, and Macrophages at Sites of Th1-Mediated Inflammation¹

David M. Frucht^2,*, Martin Aringer^*, Jérôme Galon^*, Carol Danning, Martin Brown^§, Samuel Fan^*, Michael Centola, Chang-You Wu^||, Nubuo Yamada^¶, Hani El Gabalawy and John J. O’Shea^*

^* Lymphocyte Cell Biology Section, Clinical Research Group, and Genetics Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892; ^§ Experimental Immunology Branch and ^¶ Dermatology Branch, National Cancer Institute, Bethesda, MD 20892; and ^|| Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892

Stat4 is a key transcription factor involved in promoting cell-mediated immunity, whose expression in mature cells has been reported to be restricted to T and NK cells. We demonstrate here, however, that Stat4 expression is not restricted to lymphoid cells. In their basal state, monocytes do not express Stat4. Upon activation, however, IFN-- and LPS-treated monocytes and dendritic cells express high levels of Stat4. Monocyte-expressed Stat4 in humans is phosphorylated in response to IFN-, but not IL-12. In contrast, the Th2 cytokines, IL-4 and IL-10, specifically down-regulate Stat4 expression in activated monocytes, while having little effect on Stat6 expression. Moreover, macrophages in synovial tissue obtained from patients with rheumatoid arthritis express Stat4 in vivo, suggesting a potential role in a prototypical Th1-mediated human disease. IFN--induced Stat4 activation in human monocytes represents a previously unrecognized signaling pathway at sites of Th1 inflammation.