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INFLAMMATION/IMMUNITY/MEDIATORS
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322
Submitted 25 November 2002 ; accepted in final form 28 March 2003
Toll-like receptors (TLRs) activate antimicrobial gene expression in
response to detection of specific bacterial products. Relatively little is
known about TLR5, the only TLR thought to be preferentially expressed by
epithelial cells, beyond that it confers activation of the transcription
factor NF-
B in a MyD-88 dependent manner in response to flagellin.
Because TLRs, in general, are also thought to signal through members of the
MAPK family, we examined flagellin-induced MAPK activation (via examining its
phosphorylation status) and its subsequent role in expression of the chemokine
IL-8 in polarized intestinal epithelia. Flagellin, like other proinflammatory
stimuli (TNF-
, Salmonella typhimurium), activated p38 MAPK in
a TLR5-dependent manner, whereas aflagellate bacteria or EGF did not activate
this kinase. Although ERK1 and -2 were also observed to be activated in
response to flagellin, their activation was not restricted to proinflammatory
stimuli because they were also potently activated by aflagellate bacteria
(S. typhimurium or Escherichia coli) and EGF (neither of
which activate NF-B in these cells). Pharmacological inhibition of p38
MAPK (by SB-203580) potently (IC50 = 10 nM) reduced expression of
IL-8 protein (maximal inhibition, 75%) but had no effect on NF-B
activation, only slightly attenuated upregulation of IL-8 mRNA levels in
response to flagellin, and did not effect IL-8 mRNA stability. Together, these
results indicate that epithelial TLR5 mediates p38 activation and subsequently
regulates flagellin-induced IL-8 expression independently of NF-B,
probably by influencing IL-8 mRNA translation.
flagellin; nuclear factor-B; inflammation; toll-like receptor-5; mitogen-activated protein kinase; interleukin-8
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