title: 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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, y Fisiología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Rodríguez
authors.affiliation: Departamento de Bioquímica y Biología Molecular, y Fisiología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain.
authors.forename: Saioa
authors.initials: S
authors.lastname: Márquez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-Universidad Autónoma de Madrid, Madrid, Spain.|Unidad Asociada de Biomedicina CSIC-Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.|Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la ULPGC, Las Palmas de Gran Canaria, Spain.
authors.forename: Juan Vladimir
authors.initials: JV
authors.lastname: de la Rosa
authors.affiliation: Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Alonso
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-Universidad Autónoma de Madrid, Madrid, Spain.|Unidad Asociada de Biomedicina CSIC-Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.|Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la ULPGC, Las Palmas de Gran Canaria, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Castrillo
authors.affiliation: Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Sánchez Crespo
authors.affiliation: Departamento de Bioquímica y Biología Molecular, y Fisiología, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain.|Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: Fernández
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000382:microbiology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D007370:Interferon Type I / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009181:Mycoses / Q000276:immunology*; D010766:Phosphorylation; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism*; D015054:Zymosan / Q000276:immunology
chemical_list: C508032:Ifnar1 protein, mouse; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D016753:Interleukin-10; D053633:Receptor, Interferon alpha-beta; D015054:Zymosan
keywords: cytokines; dendritic cells; fungal infection; inflammation