The expression of the beta-defensins hBD-2 and hBD-3 is differentially regulated by NF-kappaB and MAPK/AP-1 pathways in an in vitro model of Candida esophagitis.
BACKGROUND
Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions it may cause life-threatening infections like Candida sepsis. Human beta-defensins (hBDs) are critical components of host defense at mucosal surfaces and we have recently shown that hBD-2 and hBD-3 are upregulated in Candida esophagitis. We therefore studied the role of Candidate signalling pathways in order to understand the mechanisms involved in regulation of hBD-expression by C. albicans. We used the esophageal cell line OE21 and analysed the role of paracrine signals from polymorphonuclear leukocytes (PMN) in an in vitro model of esophageal candidiasis.


RESULTS
Supernatants of C. albicans or indirect coculture with C. albicans induces upregulation of hBD-2 and hBD-3 expression. PMNs strongly amplifies C. albicans-mediated induction of hBDs. By EMSA we demonstrate that C. albicans activates NF-kappaB and AP-1 in OE21 cells. Inhibition of these pathways revealed that hBD-2 expression is synergistically regulated by both NF-kappaB and AP-1. In contrast hBD-3 expression is independent of NF-kappaB and relies solely on an EGFR/MAPK/AP-1-dependent pathway.


CONCLUSIONS
Our analysis of signal transduction events demonstrate a functional interaction of epithelial cells with PMNs in response to Candida infection involving divergent signalling events that differentially govern hBD-2 and hBD-3 expression.
Steubesand
Nadine
N
Department of Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. nadine@steubesand.org
Kiehne
Karlheinz
K
Brunke
Gabriele
G
Pahl
Rene
R
Reiss
Karina
K
Herzig
Karl-Heinz
KH
Schubert
Sabine
S
Schreiber
Stefan
S
Fölsch
Ulrich R
UR
Rosenstiel
Philip
P
Arlt
Alexander
A
D002176:Candida albicans / Q000276:immunology* / Q000472:pathogenicity; D002177:Candidiasis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D018920:Coculture Techniques; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000378:metabolism; D004941:Esophagitis; D004947:Esophagus / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018928:Immunity, Mucosal; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication; D015398:Signal Transduction / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014774:Virulence; D023083:beta-Defensins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D023083:beta-Defensins; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases