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IL-4 and IL-13 Negatively Regulate TNF-- and IFN--Induced -Defensin Expression through STAT-6, Suppressor of Cytokine Signaling (SOCS)-1, and SOCS-3¹

Cristina Albanesi^*, Heather R. Fairchild, Stefania Madonna^*, Claudia Scarponi^*, Ornella De Pità^*, Donald Y. M. Leung and Michael D. Howell

^* Laboratory of Immunologia and Allergology, Istituto Dermopatico dell’Immacolata-Instituti di Recovero e Cura a Carattere Scientifico, Roma, Italy; and Division of Allergy and Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206; and Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO 80262

Human -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-/IFN- induces HBD-2 and HBD-3 by activating STAT-1 and NF-B 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-B signaling, thereby inhibiting TNF-/IFN--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 -defensin expression and represents a new therapeutic strategy for reduction of infection in human diseases associated with -defensin deficiency.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the Italian Ministry of Health (to C.A.); National Institutes of Health Grants AR41256, 5R21AR051634, National Institutes of Health/National Institute of Allergy and Infectious Diseases Contracts N01 AI40029 and N01 AI40030, General Clinical Research Center Grant MO1 RR00051 from the Division of Research Resources, the Edelstein Family Chair in Pediatric Allergy and Immunology, and the University of Colorado Cancer Center (to D.Y.M.L.).

² Address correspondence and reprint requests to Dr. Michael D. Howell, Department of Pediatrics, National Jewish Medical and Research Center, Room K1016, 1400 Jackson Street, Denver, CO 80206. E-mail address: howellm{at}njc.org

³ Abbreviations used in this paper: AMP, antimicrobial peptide; HBD, human -defensin; AD, atopic dermatitis; CF, cystic fibrosis; SOCS, suppressor of cytokine signaling; ChIP, chromatin immunoprecipitation; ODN, oligodeoxynucleotide; siRNA, short-interfering RNA; SH2, Src homology 2.

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