title: IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor of cytokine signaling (SOCS)-1, and SOCS-3.
abstract: Human beta-defensins (HBDs) are a major class of antimicrobial peptides that play an important role in the innate immune response, however, the induction and regulation of these antimicrobial peptides is not well understood. We demonstrate here that stimulation of keratinocytes with TNF-alpha/IFN-gamma induces HBD-2 and HBD-3 by activating STAT-1 and NF-kappaB signaling. We further demonstrate that IL-4 and IL-13 activate STAT-6 and induce the suppressors of cytokine signaling (SOCS)-1 and -3. This interferes with STAT-1 and NF-kappaB signaling, thereby inhibiting TNF-alpha/IFN-gamma-mediated induction of HBD-2 and HBD-3. These data suggest that targeting the STAT-1-signaling pathway or suppressor of cytokine signaling expression enhances beta-defensin expression and represents a new therapeutic strategy for reduction of infection in human diseases associated with beta-defensin deficiency.
authors.affiliation: Laboratory of Immunologia and Allergology, Istituto Dermopatico dell'Immacolata-Instituti di Recovero e Cura a Carattere Scientifico, Roma, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Albanesi
authors.forename: Heather R
authors.initials: HR
authors.lastname: Fairchild
authors.forename: Stefania
authors.initials: S
authors.lastname: Madonna
authors.forename: Claudia
authors.initials: C
authors.lastname: Scarponi
authors.forename: Ornella
authors.initials: O
authors.lastname: De Pità
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
authors.forename: Michael D
authors.initials: MD
authors.lastname: Howell
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D004789:Enzyme Activation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology* / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology* / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023083:beta-Defensins / Q000096:biosynthesis*
chemical_list: D018793:Interleukin-13; D016328:NF-kappa B; D050800:STAT6 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D015847:Interleukin-4; D007371:Interferon-gamma