Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosis factor-alpha- and IL-1beta-dependent mechanism.
Following skin sensitization a proportion of epidermal Langerhans cells (LC) are stimulated to leave the skin and to migrate, via afferent lymphatics, to draining lymph nodes where they accumulate as immunostimulatory dendritic cells (DC). It has been demonstrated previously that tumour necrosis factor-alpha (TNF-alpha), an inducible product of epidermal keratinocytes, and interleukin (IL)-1beta, produced exclusively by LC in murine epidermis, provide important signals for the initiation of this response. Recently, it has been demonstrated that IL-18, a cytokine produced by both LC and keratinocytes within the epidermis, may also participate in immune responses induced following skin sensitization. In the present investigations, the ability of IL-18 to contribute to the regulation of LC migration and the accumulation of DC in draining lymph nodes has been examined. It was found that, like IL-1beta, IL-18 administered intradermally to mice resulted in a significant reduction in epidermal major histocompatibility complex (MHC) class II+ LC densities and a marked increase in lymph node DC numbers. Using neutralizing anti-TNF-alpha and blocking anti-type I IL-1 receptor (IL-1RI) antibodies, it was shown also that the induction by IL-18 of both LC mobilization and DC accumulation in regional lymph nodes was dependent upon availability of TNF-alpha and the integrity of IL-1RI signalling. Furthermore, using IL-1beta converting enzyme (caspase-1) knockout mice, IL-18-induced LC migration was found to have a mandatory requirement for active IL-1beta. Importantly, not only was IL-18 able to contribute to the regulation of LC migration, it was found to be essential for the manifestation of these processes in response to topical sensitization with the contact allergen oxazolone.
Cumberbatch
M
M
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK and Centre for Dermatology, University College London, UK. Marie.Cumberbatch@CTL.syngenta.com
Dearman
R J
RJ
Antonopoulos
C
C
Groves
R W
RW
Kimber
I
I
D000485:Allergens / Q000276:immunology; D000818:Animals; D020170:Caspase 1 / Q000502:physiology; D002465:Cell Movement / Q000276:immunology; D004817:Epidermis / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology*; D007801:Langerhans Cells / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010081:Oxazolone / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000485:Allergens; D007375:Interleukin-1; D020382:Interleukin-18; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D010081:Oxazolone; D020170:Caspase 1