Thymic Stromal Chemokine TSLP Acts through Th2 Cytokine Production to Induce Cutaneous T-cell Lymphoma

Abstract

Thymic stromal lymphopoietin (TSLP) activates dendritic cells to induce Th2-mediated inflammation. Periostin, an extracellular matrix protein produced by fibroblasts, induces chronic inflammation by stimulating TSLP production. Recently, a reinforcing cycle linking Th2-type immune responses with periostin-induced keratinocyte activation has been proposed in atopic dermatitis pathogenesis. In this study, we investigated the role of TSLP and periostin in the development of cutaneous T-cell lymphoma (CTCL), where Th2 cytokines and chemokines are also dominant. TSLP and periostin mRNA expression levels were elevated in CTCL lesional skin, both of which correlated with IL4 expression levels. In vitro and ex vivo, IL4 or IL13 stimulated periostin expression by dermal fibroblasts, and fibroblasts from CTCL lesional skin expressed higher levels of periostin than those from control skin. Serum periostin levels of CTCL patients were also significantly higher than those of healthy individuals. Hut78 and MJ, CTCL cell lines, and peripheral blood mononuclear cells from leukemic CTCL patients expressed the TSLP receptor. TSLP induced production of IL4 and IL13 by Hut78 and MJ cells through the activation of STAT5. Moreover, TSLP induced proliferation of CTCL cells both in vitro and in vivo These data suggest that periostin-mediated TSLP production by keratinocytes directly stimulates CTCL tumor cell growth in addition to inducing a Th2-dominant tumor environment in CTCL. Cancer Res; 76(21); 6241-52. ©2016 AACR.

Interleukin-25 is involved in cutaneous T-cell lymphoma progression by establishing a T helper 2-dominant microenvironment

“…g), similar to the case in intestinal explants whose expression of IL‐25 was suppressed by TNF‐α, but there was no significant difference. We also found that periostin, which is produced by Th2 cytokine‐stimulated fibroblasts, also induced IL‐25 mRNA expression from NHEK in a dose‐dependent manner (Fig. g).…”

“…Schematic model of the main findings of this study and our previous study . Interleukin (IL)‐4 and IL‐13, produced by tumour cells and T helper (Th)2 cells in a Th2 dominant microenvironment, and periostin produced by dermal fibroblasts induced IL‐25 expression by epidermal keratinocytes.…”

“…Periostin, an extracellular matrix protein produced by Th2 cytokine‐stimulated fibroblasts, is known to promote survival and proliferation of epidermal keratinocytes and induce production of thymic stromal lymphopoietin, followed by amplification of allergic skin inflammation . In fact, periostin is highly expressed in lesional skin of AD and CTCL, and correlated with disease severity . Consequently, in addition to exposure to allergens, upregulation of Th2 cytokines and periostin contributes to IL‐25 expression by epidermal keratinocytes in lesional skin of CTCL.…”

“…30 In fact, periostin is highly expressed in lesional skin of AD and CTCL, and correlated with disease severity. 22,31 Consequently, in addition to exposure to allergens, upregulation of Th2 cytokines and periostin contributes to IL-25 expression by epidermal keratinocytes in lesional skin of CTCL.…”

Serum vascular endothelial growth factor A levels reflect itch severity in mycosis fungoides and Sézary syndrome

“…Expression of TSLP, NGF and IL‐31, which are pruritogenic molecules released by keratinocytes, is augmented in lesional skin of MF/SS . TSLP mRNA expression by HaCaT cells and NHEK was significantly elevated after administration of VEGF‐A (Fig.…”