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*
Department of Dermatology, Johns Hopkins University, Baltimore, MD 21287; and
Department of Dermatology, University G. d’Annunzio, Chieti, Italy
The epidermal Langerhans cells (LC), a member of the dendritic cell
family, and the LC-derived cytokine IL-12 play a pivotal role in the
initiation of contact hypersensitivity (CHS), a Th1 immune response in
the skin. Because IL-18, another LC-derived cytokine, shares functional
and biological properties with IL-12, we examined a potential role for
IL-18 in CHS initiation. Our studies demonstrated that during the
induction phase of murine CHS, IL-18 mRNA was significantly
up-regulated in the skin-draining lymph nodes (LN). Migratory
hapten-modified LC in LN expressed high levels of IL-18 mRNA and
secreted functional IL-18 protein. LN cells produced significant
amounts of IFN-
following in vitro IL-12 stimulation, which could be
partially blocked by anti-IL-18 Ab, suggesting a synergistic role
for endogenous IL-18 in IFN- production by LN cells. Because mature
IL-18 requires cleavage of immature precursors by caspase-1, we further
examined IL-12-induced IFN- production in caspase-1-/-
LN cells. An impaired IFN- production was seen in
caspase-1-/- LN cells, which could be restored by
addition of exogenous IL-18, supporting a role for caspase-1-cleaved,
mature IL-18 in IFN- production. Finally, in vivo studies showed
that CHS responses were significantly inhibited in mice treated with
neutralizing IL-18 Ab as well as in caspase-1-/- mice
deficient in mature IL-18, indicating functional relevance for IL-18 in
CHS. Taken together, our studies demonstrate that LC-derived IL-18
significantly contributes to CHS initiation.
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