title: Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase-dependent induction of Socs-3.
abstract: IL-25, a member of the IL-17 cytokine family, is known to enhance Th2-like responses associated with increased serum levels of IgE, IgG1, IgA, blood eosinophilia, and eosinophilic infiltrates in various tissues. However, IL-25 also abrogates inflammatory responses driven by Th17 cells. However, the cell types that respond to IL-25 and the mechanisms by which IL-25 differentially regulates immune reactions are not well explored. To identify potential targets of IL-25, we initially examined IL-25 receptor (IL-25R) in human peripheral blood cells. IL-25R was predominantly expressed by CD14(+) cells. We next assessed the functional role of IL-25 in modulating the response of CD14(+) cells to various inflammatory signals. CD14(+) cells responded to IL-25 by down-regulating the synthesis of inflammatory cytokines induced by toll-like receptor (TLR) ligands and inflammatory cytokines. Inhibition of cytokine response by IL-25 occurred via a p38 Map kinase-driven Socs-3-dependent mechanism. In vivo, IL-25 inhibited monocyte-derived cytokines and protected against LPS-induced lethal endotoxemia in mice. These data indicate that IL-25 is a negative regulator of monocyte proinflammatory cytokine responses, which may have therapeutic implications.
authors.affiliation: Department of Internal Medicine & Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, University Tor Vergata of Rome, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Sarra
authors.forename: Angelamaria
authors.initials: A
authors.lastname: Rizzo
authors.forename: Massimo C
authors.initials: MC
authors.lastname: Fantini
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Thomas T
authors.initials: TT
authors.lastname: MacDonald
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D011946:Receptors, Antigen / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C486701:IL25 protein, human; D020381:Interleukin-17; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011946:Receptors, Antigen; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases