title: The Inflammasome and the Epidermal Growth Factor Receptor (EGFR) Are Involved in the Staphylococcus aureus-Mediated Induction of IL-1alpha and IL-1beta in Human Keratinocytes.
abstract: Staphylococcus (S.) aureus is an important pathogen causing various infections including those of the skin. Keratinocytes are able to sense invading S. aureus and to initiate a fast defense reaction by the rapid release of innate defense mediators such as antimicrobial peptides and cytokines. There is increasing evidence that the cytokines IL-1alpha and IL-1beta, which both signal through the IL-1 receptor, play an important role in cutaneous defense against S. aureus. The aim of this study was to gain more insight into the underlying mechanisms leading to the S. aureus-induced IL-1alpha and IL-1beta expression in keratinocytes. Infection of human primary keratinocytes with S. aureus led to the induction of gene expression and protein secretion of IL-1alpha and IL-1beta. Full S. aureus-induced IL-1 protein release required the inflammasome components caspase-1 and ASC (apoptosis-associated speck-like protein containing a CARD) whereas gene induction of IL-1alpha and IL-beta by S. aureus was not dependent on caspase-1 and ASC. Since patients receiving anti-cancer therapy by inhibition of the epidermal growth factor receptor (EGFR) often suffer from skin infections caused by S. aureus we additionally evaluated whether the EGFR pathway may be involved in the IL-1alpha and IL-1beta induction by S. aureus. Inactivation of the EGFR with a blocking antibody decreased the S. aureus-mediated IL-1alpha and IL-1beta induction in primary keratinocytes. Moreover, the use of siRNA experiments revealed that ADAM17 (A Disintegrin and A Metalloprotease 17), a metalloproteinase known to mediate the shedding and release of EGFR ligands, was required for full induction of IL-1alpha and IL-1beta in keratinocytes infected with S. aureus. A failure of keratinocytes to adequately upregulate IL-1alpha and IL-1beta may promote S. aureus skin infections.
authors.affiliation: Department of Dermatology, University of Kiel, Kiel, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Simanski
authors.affiliation: Department of Dermatology, University of Kiel, Kiel, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Rademacher
authors.affiliation: Department of Dermatology, University of Kiel, Kiel, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Schröder
authors.affiliation: Department of Dermatology, University of Kiel, Kiel, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Gläser
authors.affiliation: Department of Dermatology, University of Kiel, Kiel, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Harder
mesh_terms: D051722:ADAM Proteins / Q000502:physiology; D000072198:ADAM17 Protein; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D053582:Interleukin-1alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism* / Q000382:microbiology; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013211:Staphylococcus aureus / Q000502:physiology*
chemical_list: D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C402202:PYCARD protein, human; D011498:Protein Precursors; D034741:RNA, Small Interfering; C512478:EGFR protein, human; D066246:ErbB Receptors; D020170:Caspase 1; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human