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Expression of Interleukin-18 and Caspase-1 in Cutaneous T-Cell Lymphoma

Authors' Affiliations: ¹ Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital; ² Biostatistics Core Facility of the Dana-Farber Harvard Cancer Center, and Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts and ³ Department of Dermatology, Mie University Faculty of Medicine, Tsu, Mie, Japan

Requests for reprints: Thomas S. Kupper, Harvard Skin Disease Research Center, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: 617-525-5550; Fax: 617-525-5571; E-mail: tskupper{at}rics.bwh.harvard.edu.

Purpose: Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing Th2 T cells. Clonal T cells and CTCL skin lesions typically express Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-10, but fail to produce Th1 cytokines. However, the reason for Th2 bias is unknown. IL-18 is a pleiotropic proinflammatory cytokine produced by monocytes/macrophages lineage as well as epithelial cells, such as human keratinocytes. In the absence of IL-12, IL-18 leads to increased immunoglobulin E production from B cells and enhanced production of IL-4 and IL-13 by basophils, mast cells, and CD4⁺ T cells. We have analyzed cytokines in CTCL patients, which may bias the immune response around the Th1/Th2 axis.

Experimental Design: We examined plasma of 95 CTCL patients and skin of 20 CTCL patients for IL-18, caspase-1, IL-12, and other cytokines. To identify the presence or absence of these cytokine proteins in CTCL and normal skin, we cultured explants from skin biopsies on three-dimensional matrices.

Results: Plasma levels of IL-18 and its converting enzyme, caspase-1, were significantly elevated in CTCL. mRNA levels for these factors were also elevated in CTCL skin lesions. Matrices populated with CTCL lesional skin produced significant amounts of IL-18 and caspase-1; however, production of IL-12 protein was barely detectable.

Conclusions: We propose that the high levels of IL-18 expression in lesional CTCL skin contribute to increased plasma levels of IL-18 and that this, in the face of significantly lower levels of IL-12, may contribute to the Th2 bias seen in this disease.