Abstract
Irritant Contact Dermatitis (ICD) is characterized by epidermal hyperplasia and inflammatory cytokine release. IL-6 has been shown to be involved in the pathogenesis of ICD; however, the involvement of the IL-22/IL-22Rα axis and its relation to IL-6 in the inflammatory response following irritant exposure are unknown. Using a chemical model of ICD, it was observed that mice with a keratinocyte-specific knockout of IL-6Rα (IL-6RαΔker) presented with increased inflammation and IL-22Rα and IL-22 protein expression relative to WT following irritant exposure, indicating that IL-6Rα deficiency in epidermal keratinocytes leads to the upregulation of IL-22Rα and its ligand during ICD. Furthermore, it was shown that IL-6 negatively regulates the expression of IL-22Rα on epidermal keratinocytes. This effect is functional as the effects of IL-22 on keratinocyte proliferation and differentiation were markedly reduced when keratinocytes were pretreated with IL-6 prior to IL-22 treatment. These results show that IL-6 modulates the IL-22/IL-22Rα axis in the skin and suggest that this occurrence may be associated with the increased epidermal hyperplasia and exacerbated inflammatory response observed in IL-6RαΔker mice during ICD.
Highlights
IL-22 is a proinflammatory cytokine that belongs to the IL-10 family of cytokines [1]
Quantitative analysis of hematoxylin and eosin (H&E) staining from lesional skin revealed that IL-6RαΔker mice presented with significantly increased epidermal hyperplasia relative to WT after seven (7) days of benzalkonium chloride (BKC) exposure (Figures 1(a)–1(e))
Based on the evidence presented we propose that during Irritant Contact Dermatitis (ICD), IL-6 limits epidermal hyperplasia via reducing the responsiveness of epidermal keratinocytes to IL-22
Summary
IL-22 is a proinflammatory cytokine that belongs to the IL-10 family of cytokines [1]. IL-22 directly acts on epithelial cells by binding to a heterodimer receptor complex made up of the IL-22 receptor alpha (IL-22Rα) and the IL-10 receptor beta (IL-10Rβ) [2, 3]. IL-22Rα is expressed primarily by epithelial cells of the skin, kidneys, and lungs, while IL-10Rβ is relatively ubiquitous [3]. Only cells that bear IL-22Rα can respond to the effects of IL-22 [4, 5]. The role of IL-22 has been widely reported in several inflammatory skin diseases. High serum levels of this cytokine have been shown to correlate with poor disease prognosis in psoriasis [13], and psoriatic skin has been shown to express higher levels of IL-22 mRNA relative to normal skin from controls [14, 15]
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