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

Abstract

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-γ- and LPS-treated monocytes and dendritic cells express high levels of Stat4. Monocyte-expressed Stat4 in humans is phosphorylated in response to IFN-α, 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-α-induced Stat4 activation in human monocytes represents a previously unrecognized signaling pathway at sites of Th1 inflammation.

The Production of IFN-γ by IL-12/IL-18-Activated Macrophages Requires STAT4 Signaling and Is Inhibited by IL-4

“…Furthermore, STAT4 protein was found in human dendritic cells, monocytes, and macrophages (18,19). Therefore, we envisaged a role of STAT4 in macrophage activation by IL-12 plus IL-18.…”

“…In contrast, in human blood monocyte-derived dendritic cells stimulation with IL-12 led to tyrosine-phosphorylation of Tyk2 and Jak2 kinase as well as of STAT3 and STAT4 (18). In LPS-activated human monocytes, STAT4 protein was shown to be expressed and tyrosine-phosphorylated on stimulation with IFN-␣ (19). However, whether NF-B, NOS2, and/or the Jak/STAT pathway are actually required for the production of IFN-␥ by dendritic cells or macrophages is unknown to date.…”

T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells

“…In contrast to the findings of Lighvani et al (42), where human monocytes treated with IFN-␥ expressed substantial levels of T-bet, we did not detect T-bet expression in peritoneal, splenic, or BM-derived macrophages after treatment with IFN-␥ or after phagocytosis of latex beads (data not shown), leading us to conclude that the production of IFN-␥ from these cells is controlled by transcription factors other than T-bet. One of these factors may well be Stat4 (46)(47)(48). Substantial differences in lineage commitment and subset profiles of DCs and macrophages have been observed between human and mouse species (5).…”

The α7 nicotinic acetylcholine receptor on fibroblast‐like synoviocytes and in synovial tissue from rheumatoid arthritis patients: A possible role for a key neurotransmitter in synovial inflammation

“…AR-R17779 is a more selective ␣7nAChR agonist, with a 35,000-fold higher selectivity and 5-fold higher affinity for the ␣7nAChR compared with nicotine (41,42). Previous in vivo studies have indicated that nicotine and ␣7-specific agonists have antiinflammatory properties.…”