title: SH2-domain mutations in STAT3 in hyper-IgE syndrome patients result in impairment of IL-10 function.
abstract: Autosomal-dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency caused by STAT3 mutations. This inherited condition is characterized by eczema, staphylococcal cold abscesses and recurrent pulmonary infections. Given that STAT3 is involved in IL-10 signaling, we examined the immunoregulatory role of IL-10 in inflammation by studying the effects of IL-10 on monocytes, neutrophils and monocyte-derived DCs from HIES subjects. Analysis of gene expression in PBMCs and neutrophils isolated from HIES patients and stimulated with LPS in the presence of IL-10 showed reduced expression of IL1RN, which encodes IL-1 receptor antagonist (IL-1ra), and SOCS3 mRNA but increased CXCL8 mRNA expression. Moreover, secretion of the anti-inflammatory protein IL-1ra was reduced in AD-HIES patients. DCs from HIES patients secreted higher levels of TNF-α, IL-6 and, to a lesser extent, IL-12 when these cells were cultured in the presence of IL-10. These results suggest that IL-10 activity is affected in myeloid cells (e.g. monocytes, DCs) of HIES patients. Impairment of IL-10 signaling in patients with AD-HIES might result in an altered balance between pro-inflammatory and anti-inflammatory signals and might lead to persistent inflammation and delayed healing after infections.
authors.affiliation: Department of Pediatrics, Institute of Molecular Medicine Angelo Nocivelli, University of Brescia, Brescia, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacomelli
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
authors.forename: Daniele
authors.initials: D
authors.lastname: Moratto
authors.forename: Patrizia
authors.initials: P
authors.lastname: Bertolini
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Ricci
authors.forename: Cristina
authors.initials: C
authors.lastname: Bertulli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Marco
authors.initials: M
authors.lastname: Cassatella
authors.forename: Flavia
authors.initials: F
authors.lastname: Bazzoni
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D007589:Job Syndrome / Q000235:genetics* / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D018909:src Homology Domains / Q000235:genetics*
chemical_list: C508606:CXCL8 protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12