Yamanaka Kei-ichi, Clark Rachael, Dowgiert Rebecca, Hurwitz Daniel, Shibata Michio, Rich Benjamin E, Hirahara Kazuki, Jones David A, Eapen Sara, Mizutani Hitoshi, Kupper Thomas S
Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA.
Clin Cancer Res. 2006 Jan 15;12(2):376-82. doi: 10.1158/1078-0432.CCR-05-1777.
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.
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.
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.
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.
皮肤T细胞淋巴瘤（CTCL）是一种归巢于皮肤的Th2 T细胞恶性肿瘤。克隆性T细胞和CTCL皮肤病变通常表达Th2细胞因子，包括白细胞介素（IL）-4、IL-5和IL-10，但不产生Th1细胞因子。然而，Th2偏向的原因尚不清楚。IL-18是一种多效性促炎细胞因子，由单核细胞/巨噬细胞谱系以及上皮细胞（如人角质形成细胞）产生。在缺乏IL-12的情况下，IL-18会导致B细胞产生的免疫球蛋白E增加，并增强嗜碱性粒细胞、肥大细胞和CD4(+) T细胞产生IL-4和IL-13。我们分析了CTCL患者的细胞因子，这些细胞因子可能会使免疫反应偏向Th1/Th2轴。
我们检测了95例CTCL患者的血浆和20例CTCL患者的皮肤中的IL-18、半胱天冬酶-1、IL-12和其他细胞因子。为了确定这些细胞因子蛋白在CTCL和正常皮肤中的存在与否，我们在三维基质上培养皮肤活检组织的外植体。
CTCL患者血浆中IL-18及其转化酶半胱天冬酶-1的水平显著升高。这些因子的mRNA水平在CTCL皮肤病变中也升高。用CTCL病变皮肤填充的基质产生了大量的IL-18和半胱天冬酶-1；然而，几乎检测不到IL-12蛋白的产生。
我们提出，CTCL病变皮肤中IL-18的高表达导致血浆中IL-18水平升高，并且在IL-12水平显著降低的情况下，这可能导致了该疾病中所见的Th2偏向。
