IL-22, but Not IL-17, Dominant Environment in Cutaneous T-cell Lymphoma

Abstract

Purpose: Both patients with cutaneous T-cell lymphoma (CTCL) and those with atopic dermatitis (AD) have pruritus, T H 2-biased T cells, and a tendency to have bacterial infections, suggesting a common pathologic basis for these two diseases. Recently, interleukin (IL)-22-producing T cells were reported in skin of patients with AD. In this study, we investigated expression levels of T H 22-and T H 17-related molecules in lesional skin and sera isolated from patients with CTCL.Experimental Design: Skin biopsies and sera were collected from patients with CTCL or psoriasis and from healthy volunteers. Protein and mRNA expression levels of IL-22, IL-17A, IL-17F, IL-23p19, IL-10, IL-4, CCL20, CCR6, IL-8, and IL-20 were examined in lesional tissue and a subset of these molecules in sera. Phosphorylation of STAT3 was also assessed in lesional skin of CTCL and psoriasis by immunohistochemistry.Results: IL-22, IL-10, IL-4, CCL20, and CCR6 mRNA and protein levels, but not IL-17A, IL-17F, IL-23p19, IL-8, or IL-20, were significantly elevated in lesional skin of CTCL. Phosphorylation of STAT3 was detected in epidermis of CTCL skin. Moreover, serum IL-22, IL-10, and CCL20 levels were increased in CTCL and correlated with disease severity.Conclusions: Our results suggest that IL-22 is important in establishing the tumor microenvironment for CTCL. Enhanced expression of CCL20 may explain epidermal hyperplasia and migration of CCR6 þ cells, such as Langerhans cells, into lesional skin. Relatively low expression of IL-17 may explain the lack of neutrophils in lesions of CTCL, which correlates with bacterial infections that commonly occur in skin affected by CTCL. Clin Cancer Res; 17(24); 7529-38. Ó2011 AACR.

Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

“…21,[57][58][59]60 The present findings offer a possible explanation for these opposing results; specifically, that the differences in frequency and severity of skin colonization and infection by SE-producing bacteria between different cohorts of patients and even within a single cohort may explain why IL-17 expression differed between these studies and between patients within a single cohort. 21,57,60 The finding that SEA induces IL-17 expression in nonmalignant primary T cells was not unexpected, given that SEA mediates STAT3 activation in these cells, 77 but it was important because it suggests that both malignant and nonmalignant T cells may contribute to IL-17 expression in vivo. Because psoriasis is also associated with IL-17, deregulated STAT3 signaling, and skin colonization by superantigen-producing bacteria like S aureus, it is tempting to speculate whether similar pathological mechanisms are involved in psoriasis and CTCL disorders, which have many histologic and clinical features in common.…”

“…Thus, some studies have reported on IL-17A and/or IL-17F expression by malignant T cells in lesional skin or blood, 21,55,57-59 whereas others did not find IL-17 family cytokines despite the presence of IL-22-producing T helper (Th)17 cells. 60 Because IL-17 is typically produced by CD4 T cells in response to bacteria such as S aureus (reviewed in Lee et al 61 ) and because SE-producing S aureus often colonizes lesional skin, we hypothesized that SE can trigger IL-17 expression in CTCL. Accordingly, we tested whether bacterial isolates from lesional skin induced IL-17 production in cocultures of malignant and nonmalignant T cells.…”

Overexpression of hypoxia‐inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides—Cutaneous T‐cell lymphoma: Clinical implications

“…1 T-cell differentiation that is predominant in the skin lesions of MF patients, [13][14][15][16][17] it has been consistently reported that the percentage of forkhead box P3 positive (FoxP3 1 ) cells decreases with disease progression.…”

Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation

“…In keeping, the malignant activity of Stat3 and the expression of IL-10 increase during disease progression in parallel with the evolving immune dysregulation. [23][24][25][26] Activation of Stat3 in malignant cells can lead to secretion of soluble mediators facilitating activation of Stat3 in infiltrating benign immune cells, thereby suppressing cell-mediated cytotoxicity and promoting accumulation of immunosuppressive regulatory T cells. Furthermore, aberrant activation of Stat3 in malignant cells can induce expression of immunoregulatory factors including IL-10.…”