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-Defensin-2 in Gingival Epithelial Cells: The Involvement of Mitogen-Activated Protein Kinase Pathways, But Not the NF-
B Transcription Factor Family1
,
,
Departments of
*
Oral Biology and
Periodontics, School of Dentistry, and Departments of
Biochemistry and
Medicine/Dermatology, School of Medicine, University of Washington, Seattle, WA 98195
Stratified epithelia of the oral cavity are continually exposed to
bacterial challenge that is initially resisted by neutrophils and
epithelial factors, including antimicrobial peptides of the
-defensin family. Previous work has shown that multiple signaling
pathways are involved in human -defensin (hBD)-2 mRNA regulation in
human gingival epithelial cells stimulated with a periodontal
bacterium, Fusobacterium nucleatum, and other
stimulants. The goal of this study was to further characterize these
pathways. The role of NF-
B in hBD-2 regulation was investigated
initially due to its importance in inflammation and infection. Nuclear
translocation of p65 and NF-B activation was seen in human gingival
epithelial cells stimulated with F. nucleatum cell wall
extract, indicating possible involvement of NF-B in hBD-2
regulation. However, hBD-2 induction by F. nucleatum was
not blocked by pretreatment with two NF-B inhibitors, pyrrolidine
dithiocarbamate and the proteasome inhibitor, MG132. To
investigate alternative modes of hBD-2 regulation, we explored
involvement of mitogen-activated protein kinase pathways. F.
nucleatum activated p38 and c-Jun
NH2-terminal kinase (JNK) pathways, whereas it had
little effect on p44/42. Furthermore, inhibition of p38 and JNK
partially blocked hBD-2 mRNA induction by F. nucleatum,
and the combination of two inhibitors completely blocked expression.
Our results suggest that NF-B is neither essential nor sufficient
for hBD-2 induction, and that hBD-2 regulation by F.
nucleatum is via p38 and JNK, while phorbol ester induces hBD-2
via the p44/42 extracellular signal-regulated kinase pathway. Studies
of hBD-2 regulation provide insight into how its expression may be
enhanced to control infection locally within the mucosa and thereby
reduce microbial invasion into the underlying
tissue.
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