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.