IL-25 is involved in CTCL progression by establishing Th2-dominant microenvironment

Summary

Background

Interleukin (IL)-25 is a member of the IL-17 family which can promote and augment T-helper type (Th) 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.

Objective

To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL).

Methods

Expression and localization of IL-25 in lesional skin was investigated using 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 tumor cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in Sézary syndrome patients.

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 (stage IIB-IV) 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 STAT6. Peripheral blood mononuclear cells from one patient with Sézary 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 Th2-dominant microenvironment through the direct induction of IL-13 by tumor cells.

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