IL-33 and IL-1F9 in allergic contact dermatitis

Background: Allergic contact dermatitis (ACD) is a delayed type IV or cell-mediated hypersensitivity resulting from cutaneous contact with a specific allergen. Erythema, edema, and vesiculation represent the classical clinical manifestations. Several pro-inflammatory cytokines are involved in the immunopathogenesis of ACD, but little is known about the role of interleukin (IL)-1 family. These evolutionarily ancient cytokines act on innate immune cells to influence their survival and function. In addition, they act directly on lymphocytes to reinforce adaptive immune responses. The IL-1 family members are among the most potent molecules of the innate immune system. One group consists of IL-1F1 and IL-1F2 as pro-inflammatory mediators and their antagonist IL-1F3. A second functional group is formed by IL-1F6, IL-1F8 and IL-1F9 as pro-inflammatory mediators and their corresponding antagonist IL-1F5. IL-33 is the most recently identified IL-1 family member and is detected in the nucleus of epithelial cells of tissues in contact with the environment. Because of its distribution at "border" tissues, IL-33 has been supposed to function as "alarmin" which, similarly to IL-1α, may alert the immune system after cell and tissue damage. It may primarily act through a T helper (Th) 2 pathway but can, under certain conditions, promote Th1-type responses. IL-1F9, a pro-inflammatory member of IL-1 family, is mostly expressed in keratinocytes after stimulation with Th1 cytokines. The presence of IL-1F9 in epithelial barriers suggests that this novel interleukin fulfils similar roles as their known family members (IL- 1α and IL-1β), promoting response to injury or infection. Objective: To assess the role of IL-33 and IL-1F9 in ACD and to evaluate the "ex vivo skin organ culture" as a system to investigate the regulatory mechanism involved in this disease. Materials and methods: IL-33 and IL-1F9 mRNA were quantified in lesional and non lesional skin of 12 ACD patients and in matched healthy donors through quantitative reverse transcription polymerase chain reaction (qRT-PCR). 3 mm punch biopsies from non lesional skin of 4 ACD patients and from healthy controls, who had undergone plastic surgery, were cultured and stimulated by application of the positive allergen onto the epidermis for 72 hrs. IL-33 and IL-1F9 expression levels were detected through qRT-PCR. Results: Our results show that IL-33 and IL-1F9 are similarly expressed in allergic skin when compared with non lesional skin, and their expression is even higher when compared with healthy controls. Moreover, these two interleukins are augmented in "ex vivo skin organ culture" of non lesional skin after the exposure to the allergen, while no increase was detected in normal skin, when treated with different allergens. Conclusions: IL-33 and IL-1F9 are involved in the immunopathogenesis of ACD. Allergic patients have basal higher expression of IL-33 and IL-1F9, which is increased after hapten re-exposure. Skin organ culture confirmed these results, representing a robust platform on which the immune aspects of ACD can be investigated.