title: IL-1β and ADAM17 are central regulators of β-defensin expression in Candida esophagitis.
abstract: Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions, it may cause life-threatening infections, including Candida sepsis. We have recently shown that human β-defensins (hBDs) hBD-2 and hBD-3 are upregulated in Candida esophagitis and that this antifungal host response is distinctly regulated by NF-κB and MAPK/activator protein-1 (AP-1) pathways. Here, we show that C. albicans induces hBD-2 through an autocrine IL-1β loop and that activation of the epidermal growth factor receptor (EGFR) by endogenous transforming growth factor-α (TGF-α) is a crucial event in the induction of hBD-3. To further dissect upstream signaling events, we investigated expression of the central sheddases for EGFR ligands ADAM10 and ADAM17 in the healthy and infected esophagus. Next, we used pharmaceutical inhibitors and small-interfering RNA-mediated knock down of ADAM10 and ADAM17 to reveal that ADAM17-induced shedding of TGF-α is a crucial step in the induction of hBD-3 expression in response to Candida infection. In conclusion, we describe for the first time an autocrine IL-1β loop responsible for the induction of hBD-2 expression and an ADAM17-TGF-α-EGFR-MAPK/AP-1 pathway leading to hBD-3 upregulation in the course of a Candida infection of the esophagus.
authors.affiliation: Department of Internal Medicine I, University of Kiel, Germany University Hospital Schleswig-Holstein, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Pahl
authors.forename: Gabriele
authors.initials: G
authors.lastname: Brunke
authors.forename: Nadine
authors.initials: N
authors.lastname: Steubesand
authors.forename: Sabine
authors.initials: S
authors.lastname: Schubert
authors.forename: Martina
authors.initials: M
authors.lastname: Böttner
authors.forename: Thilo
authors.initials: T
authors.lastname: Wedel
authors.forename: Christian
authors.initials: C
authors.lastname: Jürgensen
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Heiner
authors.initials: H
authors.lastname: Schäfer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeissig
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Karina
authors.initials: K
authors.lastname: Reiss
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D002175:Candida / Q000235:genetics / Q000378:metabolism; D002177:Candidiasis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004941:Esophagitis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D004947:Esophagus / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D023083:beta-Defensins; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human