SH2-domain mutations in STAT3 in hyper-IgE syndrome patients result in impairment of IL-10 function

Mauro Giacomelli; Nicola Tamassia; Daniele Moratto; Patrizia Bertolini; Giampaolo Ricci; Cristina Bertulli; Alessandro Plebani; Marco Cassatella; Flavia Bazzoni; Raffaele Badolato

doi:10.1002/eji.201141721

SH2-domain mutations in STAT3 in hyper-IgE syndrome patients result in impairment of IL-10 function

Eur J Immunol. 2011 Oct;41(10):3075-84. doi: 10.1002/eji.201141721. Epub 2011 Sep 6.

Authors

Mauro Giacomelli¹, Nicola Tamassia, Daniele Moratto, Patrizia Bertolini, Giampaolo Ricci, Cristina Bertulli, Alessandro Plebani, Marco Cassatella, Flavia Bazzoni, Raffaele Badolato

Affiliation

¹ Department of Pediatrics, Institute of Molecular Medicine Angelo Nocivelli, University of Brescia, Brescia, Italy.

PMID: 21792878
DOI: 10.1002/eji.201141721

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Base Sequence
Cells, Cultured
Child
Child, Preschool
Dendritic Cells / immunology
Female
Gene Expression Profiling
Humans
Interleukin 1 Receptor Antagonist Protein / biosynthesis
Interleukin 1 Receptor Antagonist Protein / deficiency
Interleukin 1 Receptor Antagonist Protein / genetics
Interleukin-10 / immunology
Interleukin-10 / metabolism*
Interleukin-12 / biosynthesis
Interleukin-6 / biosynthesis
Interleukin-8 / biosynthesis
Interleukin-8 / genetics
Job Syndrome / genetics*
Job Syndrome / immunology*
Lipopolysaccharides / immunology
Male
Monocytes / immunology
Myeloid Cells / immunology
Myeloid Cells / metabolism
Neutrophils / immunology
Phosphorylation
RNA, Messenger / biosynthesis
STAT3 Transcription Factor / chemistry
STAT3 Transcription Factor / genetics*
STAT3 Transcription Factor / metabolism
Sequence Analysis, DNA
Signal Transduction
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins / biosynthesis
Suppressor of Cytokine Signaling Proteins / deficiency
Suppressor of Cytokine Signaling Proteins / genetics
Tumor Necrosis Factor-alpha / biosynthesis
src Homology Domains / genetics*

Substances

CXCL8 protein, human
IL1RN protein, human
Interleukin 1 Receptor Antagonist Protein
Interleukin-6
Interleukin-8
Lipopolysaccharides
RNA, Messenger
SOCS3 protein, human
STAT3 Transcription Factor
STAT3 protein, human
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins
Tumor Necrosis Factor-alpha
Interleukin-10
Interleukin-12