IL32 Is Progressively Expressed in Mycosis Fungoides Independent of Helper T-cell 2 and Helper T-cell 9 Polarization

Abstract

Mycosis Fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL) is characterized by a helper T cell 2 (Th2)-skewing with a mature CD4+ memory T-cell phenotype. Using skin samples from MF patients (n=21), healthy volunteers (n=17), individuals with atopic dermatitis (n=17) and psoriasis (n=9), we found interleukin (IL)-32 mRNA expression significantly higher in MF samples than in samples from benign inflammatory skin diseases, and its expression increases with disease progression. By immunohistochemistry and immunofluorescence, we confirmed IL-32 protein expression in many CD3+CD4+ T cells and some epidermotropic T cells in MF lesions. MyLa cells (a MF cell line) express IL-32, which in turn could promote cellular proliferation and viability in a dose-dependent fashion. IL-32-treated MyLa and CTCL HH cells up-regulated cell proliferation and survival genes. Of the major “polarizing” T-cell cytokines, only IFNγ mRNA increases with MF progression and positively correlates with IL-32 mRNA expression. Th2 cytokines do not positively correlate with IL-32 mRNA expression or MF progression. Furthermore, by flow cytometry, IL-32 production by circulating activated T-cells in healthy individuals was found in both IFNγ+ and IFNγ− cells but not in IL-4+ or IL-13+ cells. In conclusion, we have identified IL-32+ cells as the likely tumor cells in MF, and demonstrated that IL-32 mRNA expression increases with MF progression and is significantly higher than those in other skin diseases, and that some IL-32+ T cells are independent from the defined Th subsets. Thus IL-32 may play a unique role in MF progression as an autocrine cytokine.

IL-32 induces indoleamine 2,3-dioxygenase+CD1c+ dendritic cells and indoleamine 2,3-dioxygenase+CD163+ macrophages: Relevance to mycosis fungoides progression

“…We previously showed that IL-4 mRNA expression levels in MF skin were not significantly higher than those in healthy volunteers. 7 Additionally, we confirm that MF skin shows significantly higher GM-CSF mRNA expression compared to healthy volunteers (Fig. S1).…”

“…Previously, we 7 and others 8,9 reported that IL-32, a proinflammatory cytokine, is highly and progressively expressed in MF skin. We also showed that MF tumor cells are regarded as the most probable candidates for expressing IL-32.…”

“…IL-32 promotes proliferation and survival of tumor cells in MF, and among many cytokines that we examined, IL-32 messenger RNA (mRNA) expression level is most strongly related to disease progression. 7 These facts indicate that IL-32 plays important roles in the pathogenesis of MF. Here …”

Risk Factors for Skin Infections in Mycosis Fungoides

“…Interferon-γ and interleukin (IL)-32 mRNA expression levels are increased in MF skin compared to normal and benign inflammatory dermatoses [28] . In vitro, IL-32 inhibits HSV-2 growth in epithelial Vero cells [29] .…”

Recent advances in primary cutaneous T-cell lymphoma

“…A study by Ohmatsu et al [35] demonstrates elevated interleukin-32 mRNA expression levels in mycosis fungoides and suggests that interleukin-32 might contribute to the disease progression. Another study from Singer et al [36] reports on elevated serum levels of interleukin-31 in 14 of 26 pruritic Sézary syndrome patients.…”