Interleukin-25 Is Involved In Cutaneous T-Cell Lymphoma Progression By Establishing A T Helper 2-Dominant Microenvironment

Background Interleukin (IL)-25 is a member of the IL-17 family, which can promote and augment T-helper (Th) type 2 responses. The expression of IL-25 and its cognate receptor, IL-25 receptor (IL-25R), is upregulated and correlated with disease activity in Th2-associated diseases.Objectives To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL).Methods Expression and location of IL-25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL-25 production from normal human epidermal keratinocytes was assessed by quantitative reverse-transcription real-time polymerase chain reaction. Serum IL-25 levels were measured by enzyme-linked immunosorbent assay. The direct effect of IL-25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sezary syndrome.Results IL-25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL-4 and IL-13, and periostin induced IL-25 expression by normal human epidermal keratinocytes. Serum IL-25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL-25R and its expression was augmented by stimulation with IL-25. IL-25 enhanced IL-13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sezary syndrome expressed IL-25R and showed increase of IL-13 production by IL-25.Conclusions Th2 cytokines highly expressed in CTCL lesional skin induce IL-25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2-dominant microenvironment through the direct induction of IL-13 by tumour cells.What's already known about this topic?Cutaneous T-cell lymphomas (CTCLs), such as mycosis fungoides and Sezary syndrome, are regarded as T helper 2 (Th2)-type diseases, and a Th2-dominant microenvironment is beneficial for tumour cells.Interleukin (IL)-25 has the capacity to promote and augment Th2 responses and is associated with several Th2-type diseases, including atopic dermatitis.What does this study add?Th2 cytokines highly expressed in lesional skin of CTCL induce IL-25 production by epidermal keratinocytes.IL-25 directly induces IL-13 production from CTCL tumour cells through signal transducer and activator of transcription 6 (STAT6) signalling pathways, resulting in the formation of a Th2-dominant microenvironment.What is the translational message?Our results support the notion that activation of STAT6 is a key signalling pathway for the creation of a Th2-dominant microenvironment in CTCL.As the destruction of a Th2-dominant microenvironment is effective for CTCL, IL-25 and STAT6 can be a therapeutic target for CTCL.