Atopic dermatitis (AD), a common chronic inflammatory skin disease, is characterized by inflammatory cell skin infiltration. The JAK-STAT pathway has been shown to play an essential role in the dysregulation of immune responses in AD, including the exaggeration of Th2 cell response, the activation of eosinophils, the maturation of B cells, and the suppression of regulatory T cells (Tregs). In addition, the JAK-STAT pathway, activated by IL-4, also plays a critical role in the pathogenesis of AD by upregulating epidermal chemokines, pro-inflammatroy cytokines, and pro-angiogenic factors as well as by downregulating antimicrobial peptides (AMPs) and factors responsible for skin barrier function. In this review, we will highlight the recent advances in our understanding of the JAK-STAT pathway in the pathogenesis of AD.

We investigated cytokine profiles in interleukin (IL)‐4 transgenic (Tg) mice with a skin inflammatory disease resembling human atopic dermatitis. cDNA microarray revealed that the mRNAs encoding IL‐1β, IL‐2, IL‐3, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12p40, IL‐13, tumour necrosis factor (TNF)‐α, TNF‐β and interferon (IFN)‐γ were up‐regulated in the skin of late lesion Tg mice and to a lesser degree in non‐lesion Tg mice when compared to those of non‐Tg mice. Real time reverse transcription–polymerase chain reaction (RT‐PCR) analyses indicated that the cDNA copy numbers of IL‐1β, IL‐4, IL‐6, IL‐10, TNF‐α and IFN‐γ from the skin of late, early and non‐lesions increased significantly compared to non‐Tg mice. IL‐2 and IL‐12p40 cDNA copy numbers were increased significantly in early, but not late, lesions. Interestingly, IL‐1β, IL‐3, IL‐4, IL‐5, IL‐6, IL‐10, IL‐13, TNF‐α, and IFN‐γ cDNAs were increased significantly the skin of before‐onset and/or non‐lesion mice. Flow cytometry analyses demonstrated an increased percentage of keratinocytes producing IL‐4 as the disease progressed. The percentage of IL‐2, IL‐4, IL‐10 and IFN‐γ‐producing T cells and IL‐12‐producing antigen‐presenting cells in skin‐draining lymph nodes and inflammatory skin also increased, particularly in mice with late lesion. These results suggest that disease induction is primarily triggered by Th2 cytokines and that Th1, Th2 and non‐Th proinflammatory cytokines are all involved in the disease process.

Skin barrier defects play an important role in atopic dermatitis (AD) pathogenesis. Loricrin, an important barrier protein suppressed in human AD, is down-regulated by IL-4 in keratinocytes. However, the molecular mechanism is unknown. Since loricrin transcription requires p300/CBP, and Stat6 also recruits this common coactivator for its stimulated factors, we hypothesize that IL-4-activated Stat6 competes for the available endogenous p300/CBP, leading to loricrin transcription inhibition. First, we showed that loricrin is suppressed in the skin of IL-4 transgenic mice, an AD mouse model. In human keratinocytes, IL-4 down-regulation of loricrin is abrogated by a pan-Jak inhibitor, suggesting that the Jak-Stat pathway is involved. To further investigate the downstream molecular mechanism, we transfected HaCat cells with a loricrin promoter and then treated them with either IL-4 or vehicle. Not surprisingly, IL-4 greatly suppressed the promoter activity. Interestingly, this suppression was prevented when we knocked down Stat6, indicating that Stat6 participates in IL-4 regulation of loricrin. A Stat6-specific inhibitor confirmed the knockdown study. Finally, IL-4 suppression of loricrin was reversed with transfection of a CBP expression vector in a dose-dependent manner. Taken together, for the first time, we delineate a molecular mechanism for IL-4 down-regulation of loricin expression in human keratinocytes, which may play an important role in AD pathogenesis.