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Abstract
The chemokine CCL27 attracts skin-homing T cells. CCL27 production by keratinocytes
is enhanced in skin lesions from patients with atopic dermatitis or psoriasis vulgaris.
It is suggested that prostaglandin E(2) (PGE(2)) regulates skin inflammation.
We examined the in vitro effects of PGE(2) on CCL27 production in human keratinocytes.
Keratinocytes were incubated with TNF-alpha in the presence or absence of PGE(2) .
CCL27 secretion and mRNA level were analyzed by means of ELISA and RT-PCR, respectively.
Nuclear factor kappaB (NF-kappaB)-dependent transcriptional activity was analyzed
by using luciferase assays.
TNF-alpha increased CCL27 secretion and mRNA levels in parallel to NF-kappaB activity
in keratinocytes. NF-kappaB p50 or p65 antisense oligonucleotides suppressed TNF-alpha-induced
CCL27 production, indicating the requirement of NF-kappaB for CCL27 production. PGE(2)
, EP2, or EP3 agonists reduced TNF-alpha-induced CCL27 secretion and mRNA levels in
parallel to NF-kappaB activity and CCL2, CCL5, CXCL8, and CXCL10 mRNA levels. Either
EP3-specific or dual EP1-EP2 antagonist partially blocked the inhibitory effects of
PGE(2) on CCL27 production and NF-kappaB activity, and the addition of both completely
abrogated the inhibition, whereas EP1 or EP4 antagonists were ineffective. Intracellular
Ca(2+) chelator BAPTA/AM or cyclic adenosine monophosphate (cAMP)-dependent protein
kinase inhibitor H-89 partially blocked the inhibitory effects of PGE(2) on CCL27
production and NF-kappaB activity, and the addition of both completely abrogated the
inhibition. PGE(2) or EP3 agonist increased intracellular Ca(2+) concentrations. PGE(2)
or EP2 agonist increased intracellular cAMP concentrations.
PGE(2) might suppress CCL27 production by inhibiting NF-kappaB activity through EP2-mediated
cAMP and EP3-mediated Ca(2+) signals. PGE 2 might terminate T cell-mediated skin inflammation
by inhibiting CCL27 production.