Fungal pattern receptors down‐regulate the inflammatory response by a cross‐inhibitory mechanism independent of interleukin‐10 production

Abstract

Cyclic AMP regulatory element binding protein and signal transducer and activator of transcription 3 (STAT3) may control inflammation by several mechanisms, one of the best characterized is the induction of the expression of the anti-inflammatory cytokine interleukin-10 (IL-10). STAT3 also down-regulates the production of pro-inflammatory cytokines induced by immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors, a mechanism termed cross-inhibition. Because signalling via ITAM-dependent mechanisms is a hallmark of fungal pattern receptors, STAT3 activation might be involved in the cross-inhibition associated with invasive fungal infections. The fungal surrogate zymosan produced the phosphorylation of Y705-STAT3 and the expression of Ifnb1 and Socs3, but did not induce the interferon (IFN)-signature cytokines Cxcl9 and Cxcl10 in bone marrow-derived dendritic cells. Unlike lipopolysaccharide (LPS), zymosan induced IL-10 and phosphorylated Y705-STAT3 to a similar extent in Irf3 and Ifnar1 knockout and wild-type mice. Human dendritic cells showed similar results, although the induction of IFNB1 was less prominent. These results indicate that LPS and zymosan activate STAT3 through different routes. Whereas type I IFN is the main effector of LPS effect, the mechanism involved in Y705-STAT3 phosphorylation by zymosan is more complex, cannot be associated with type I IFN, IL-6 or granulocyte-macrophage colony-stimulating factor, and seems dependent on several factors given that it was partially inhibited by the platelet-activating factor antagonist WEB2086 and high concentrations of COX inhibitors, p38 mitogen-activate protein kinase inhibitors, and blockade of tumour necrosis factor-α function. Altogether, these results indicate that fungal pattern receptors share with other ITAM-coupled receptors the capacity to produce cross-inhibition through a mechanism involving STAT3 and induction of SOCS3 and IL-10, but that cannot be explained through type I IFN signalling.

Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

“…A recently report has shown that IL-10 production in human monocyte-derived DCs was increased by zymosan stimulus, which induced STAT3 Tyr705 phosphorylation. It was also observed that when cells were stimulated in the presence of WEB2086, STAT3 Tyr705 phosphorylation was reduced [42]. These data reinforce our findings in associating PAFR/STAT3 activation in IL-10 production in DCs.…”

Endoplasmic Reticulum Stress Sensor IRE1α Enhances IL-23 Expression by Human Dendritic Cells

“…This explains a positive feedback loop between HIF1 and STAT3 since Y705-STAT3 activates HIF1α transcription ( 36 , 37 ). In a previous study, we observed that both zymosan and LPS are robust activators of Y705-STAT3 phosphorylation through the induction of secondary mediators ( 38 ). In keeping with that report, the assay of P-Y705-STAT3 in nuclear extracts showed a time-course compatible with its involvement in HIF1α expression (Figure 2 A).…”

Shaping the Innate Immune Response by Dietary Glucans: Any Role in the Control of Cancer?

“…Moreover, yeast-derived β-glucans induce DC maturation, significantly increase tumor-specific cytotoxic T lymphocyte (CTL) responses [53] and program DC to express cell adhesion and migration mediators, antimicrobial molecules, and Th17-polarizing factors [54]. Furthermore, the role of secondary mediators, which include lipids, in the induction of the cytokine signature was demonstrated in DC stimulated with zymosan, a cell-wall extract from Saccharomyces cerevisiae that contains a β-glucan component, providing mechanistic clues that β-glucans can modulate the immune response by acting on the lipid mediator cascade and by activating STAT3 signaling [55,56]. The regulation of additional cellular responses by mushroom-derived β-glucans in monocytes and DC has been also described.…”