Epidermal cytokines: Homeostasis and the regulation of langerhans cell migration and cutaneous immunity

Langerhans cells (LC) are bone marrow derived professional antigen presenting cells that migrate rapidly from epidermis to lymph node following epicutaneous application of allergen. A number of cytokines, most notably interleukin (IL)-l[beta] and tumour necrosis factor-[alpha] (TNF-[alpha]) have been shown to be important in initiation of LC migration. IL-1[beta] requires cleavage by the cysteine protease caspase-1 to release its biologically active form. In view of the role of caspase-1 in regulating the processing and release of IL-l[beta], caspase-1 deficient (-/-) mice and specific caspase inhibitors were used to define the role of caspase-1 in LC migration and induction of murine contact hypersensitivity (CHS). Hapten-induced migration was impaired and CHS was suppressed in caspase-1 -/- mice. In parallel, YVAD, a caspase-1 inhibitor, prevented LC migration both in vivo and in vitro and suppressed CHS in vivo. The potential influence of IL-18, a cytokine structurally similar to IL-1[beta], on LC mobilisation and CHS was next examined. Intradermal injection of rMuIL-18 caused significant LC migration in BALB/c mice. Furthermore, allergen-induced LC migration was absent in IL-18 -/- mice. CHS was suppressed in IL-18 -/- mice, but could be restored by intradermal IL-18 pre-treatment prior to sensitisation. Parallel studies showed that IL-18 acts proximally to IL-l[beta] and TNF-[alpha]. In addition, it was shown that IL-18 was not involved in irritant contact dermatitis (ICD) and thus, this cytokine is a differentiating signal between CHS and ICD. The numerous control mechanisms of the IL-1 system within the epidermis suggest that a co-ordinated regulation is essential in the cutaneous microenvironment. Mice over-expressing either IL-l[alpha] or sIL-1 receptor antagonist in basal keratinocytes and a murine keratinocyte line were used to examine whether such homeostatic mechanisms occur both in vitro and in vivo in the epidermis. The data revealed from these studies suggest that there is a complex regulatory mechanism in which not only increased levels of IL-1 agonist lead to increases in antagonist production, but also that enhanced IL-1 receptor antagonist release results in increased production of agonist. The mobilisation of LC and their directed migration from the epidermis to draining lymph nodes are processes of pivotal importance in the generation of cutaneous immune responses. The data presented in this thesis provided important information on the role of the IL-1 system in the initiation and regulation of skin immune responses