Expression of Constitutively Active STAT3 Can Replicate the Cytokine-suppressive Activity of Interleukin-10 in Human Primary Macrophages

Abstract

There is general agreement that signal transducer and activation of transcription 3 (STAT3) is required to mediate the antiinflammatory activities of interleukin (IL)-10. However, STAT3 is activated by multiple factors that do not share the anti-inflammatory activity of IL-10. The question remains whether STAT3 is sufficient for the anti-inflammatory effects or whether there are other signals required, as had been suggested previously. We set out to map the human IL-10 receptor and to identify the key elements involved in transducing the cytokine-suppressive effects of IL-10. We were able to show an absolute requirement for both of the tyrosine residues found within the YXXQ-STAT3-docking site within the IL-10 receptor 1 and that no other signals appeared to be required. We used a constitutively active STAT3 to determine whether expression of this factor could suppress lipopolysaccharide-induced tumor necrosis factor and IL-6 production. Our data show that STAT3 activity can suppress both IL-6 and tumor necrosis factor production in lipopolysaccharide-stimulated macrophages. However, in synovial fibroblasts, STAT3 did not suppress IL-6 production, suggesting that the cellular environment plays an important role in dictating whether STAT3 drives a pro-or anti-inflammatory response.

The Interaction of ApoA-I and ABCA1 Triggers Signal Transduction Pathways to Mediate Efflux of Cellular Lipids

“…The interaction of apoA-I with ABCA1 in macrophages suppressed the lysopolysaccaride-induced secretion of the inflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α, which was reversed by silencing STAT3 or ABCA1. Thus, the apoA-I/ABCA1 interaction activates the JAK2/STAT3 pathway (57), which is antiinflammatory in macrophages (69)(70)(71)(72). Our studies also demonstrate IFN-γ may first downregulate expression of LXRα through the JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophage-derived foam cells (71,73).…”

Both STAT3 activation and cholesterol efflux contribute to the anti-inflammatory effect of apoA-I/ABCA1 interaction in macrophages

“…The STAT3 pathway is well known to have an anti-inflammatory function in macrophages (25)(26)(27). In fact, constitutive activation of STAT3 is sufficient to block most of the activated macrophage production of inflammatory cytokines (28). We have shown that the interaction of apoA-I or its mimetic peptides with ABCA1-expressing macrophages activates STAT3 and markedly suppresses the expression of proinflammatory cytokines (24).…”

The JAK-STAT Signaling Pathway: Input and Output Integration

“…The major function of IL-10 is to negatively regulate inflammatory responses from activated macrophages and dendritic cells (63). The inhibitory effects of IL-10 are mediated solely by STAT3 and are indirect (63)(64)(65)(66). That is, IL-10-mediated activation of STAT3 targets one or more STAT3-regulated genes whose products are responsible for inhibiting inflammatory gene expression at the level of transcription.…”