Increased IL-26 Expression Promotes T Helper Type 17- and T Helper Type 2-Associated Cytokine Production by Keratinocytes in Atopic Dermatitis

Abstract

Whereas atopic dermatitis (AD) is considered as a T helper 2 (Th2)-centered disease, IL-17eproducing Th (Th17) cells are also activated in AD lesional skin. However, the relationship between Th17 responses and Th2 responses in AD is still to be elucidated. Although Th17 cells are increased in AD skin, the expression and function of IL-26, which is also produced by Th17 cells, in AD are still unknown. In this report, we demonstrated that IL-26 mRNA expression levels were elevated in AD lesional skin compared with healthy controls and that IL-26-producing cells were increased in AD lesional skin by immunohistochemistry. Furthermore, IL-26 promoted IL-8, IL-1b, chemokine (C-C motif) ligand 20, IL-33, and b-defensin 2 production in keratinocytes through phosphorylation of signal transducer and activator of transcription 1 and signal transducer and activator of transcription 3. Selective JAK inhibitors for JAK1, JAK2, and tyrosine kinase 2 blocked IL-26einduced cytokine production in keratinocytes. We also showed that injection of IL-26 exacerbated an oxazolone-induced AD mouse model and upregulated Th2 and Th17 cytokine expression in vivo. Because previous studies indicate that the above molecules induced by IL-26 can promote Th17 and/or Th2 immune responses, IL-26 may play an important role for bridging between Th17 and Th2 responses, resulting in the development of AD.

Single-cell transcriptomics combined with interstitial fluid proteomics defines cell type–specific immune regulation in atopic dermatitis

“…Cluster 1 showed increased expression of KLF2 (Fig E11, C), a transcription factor involved in T cell homeostasis mediating quiescence and survival, that is present in naive as well as quiescent mature memory T cells, being downregulated upon T-cell receptor-mediated activation. 51 Thus, we conclude that cluster 1 represents quiescent memory T cells, while cluster 0 harbors activated memory T cells with effector functions mediated by active production of proinflammatory cytokines such as the T H 2-and T H 22-associated mediators IL13 and IL22, respectively, but also of the T H 17-associated [52][53][54] cytokine IL26 (Fig 7, C-E, and E11, C), despite low-to-absent IL17 expression ( Fig E11, G). These cytokines were also found in proliferating (ie, MKI671) ( Fig E11, C) cells of cluster 4 (Fig 7, C-E).…”

“…68 In line, Wolk et al 68 have shown that incubation of T H 17 cells with the IL-4 receptor a ligands IL-4 and IL-13 abrogate the production of IL-17, but not of IL-26, 68 and that IL-26 can promote T H 2-associated cytokine production by KCs in AD. 54 There are several limitations that need to be taken into account. For single-cell transcriptomics, there is currently no standardized bioinformatics approach for analysis due to the novelty of this method.…”

The Role of Th17-Related Cytokines in Atopic Dermatitis

“…IL-26 is another cytokine produced by Th17 cells. It was recently reported that IL-26 mRNA expression levels were elevated in AD lesional skin compared with healthy controls and that IL-26-producing cells were increased in AD lesional skin by immunohistochemistry [40]. IL-26 may play an important role for bridging between Th17 and Th2 responses, resulting in the development of AD.…”

Emerging Topical and Systemic JAK Inhibitors in Dermatology

“…Historically, AD is thought to be a Th2 dominated disease. Nonetheless, there is growing evidence that the immunological environment of AD is not solely defined by Th2 cells and related cytokines (IL-4, IL-5, IL-10, IL-13, and IL-31) but also by cytokines linked to other Th cell responses such as IFN-γ (Th1), IL17, or IL-22 (Th17) and IL-33 (an alarmin) (8, 52–56). Dupilumab, a mab against IL-4Rα has shown efficacy in a large number of patients and is the first approved biological for AD (57).…”