Journal of Leukocyte Biology
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Published online before print November 5, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0604352

Received for publication June 21, 2004.
Revised August 8, 2007.
Accepted for publication August 30, 2007.

Article

IL-18 is a key proximal mediator of contact hypersensitivity and allergen-induced Langerhans cell migration in murine epidermis

Christos Antonopoulos *, Marie Cumberbatch {dagger}, John B. Mee *, Rebecca J. Dearman {dagger}, Xiao-Qing Wei {ddagger}, Foo Y. Liew {sect}, Ian Kimber {dagger}, and Richard W. Groves *@

*St. John’s Institute of Dermatology, King’s College London, London, United Kingdom; {dagger}Syngenta Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom; {ddagger}School of Dentistry, Cardiff University, Cardiff, United Kingdom; and {sect}Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom

@ To whom correspondence should be addressed. E-mail: richard.groves{at}kcl.ac.uk.


  Abstract

Langerhans cells (LC) migrate rapidly from epidermis to lymph node following epicutaneous application of antigen. In this study, we have explored the role of IL-18, a cytokine with structural similarities to IL-1{beta}, in murine LC migration and contact hypersensitivity (CHS), which to oxazolone (OX) and 2-4,dinitrofluorobenzene (DNFB) was suppressed significantly in IL-18 knockout (IL-18-/-) mice and could be rescued by local intradermal administration of IL-18 prior to sensitization, suggesting that the defect in these mice was in the afferent phase of CHS. To determine the effect of IL-18 on LC migration, mice were treated topically with OX or DNFB, and remaining LC numbers were assessed. A significant decline in remaining epidermal LC occurred in wild-type (WT) mice but did not occur in IL-18-/- mice. Sodium lauryl sulfate, a nonantigenic LC migratory stimulus, induced equivalent LC migration in IL-18-/- and WT mice. In IL-18-/- mice, IL-1{beta} and TNF-{alpha} were equally able to mobilize LC from epidermis, indicating that migration in response to these cytokines is not dependent on IL-18 and suggesting that IL-18 acts upstream of these cytokines in the initiation of antigen-induced LC migration. Moreover, IL-1{beta} but not IL-18 was able to rescue the defective CHS response observed in caspase-1-/- mice, which have no functional IL-1{beta} or IL-18. These data indicate that IL-18 is a key proximal mediator of LC migration and CHS, acting upstream of IL-1{beta} and TNF-{alpha}, and may play a central role in regulation of cutaneous immune responses.

Key Words: oxazolone • lymph nodes • caspase-1






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