Evidence for a Pathogenetic Cutaneous Lupus Role of Interleukin-18 in Erythematosus

Objective. Cutaneous manifestations are the most common clinical features of lupus erythematosus (LE). The aim of this study was to analyze differences in the inflammatory response of keratinocytes from patients with cutaneous LE (CLE) compared with healthy controls. Methods. Keratinocytes from LE patients and controls were cultured from epidermal stem cells of the hair follicle of anagen head hairs. Functional responses of keratinocytes to cytokine stimulation were determined by How cytometry and enzyme-linked immunosorbent assay. Biopsy samples of lesional skin were analyzed by immunohistochemistry. Results. Keratinocytes from CLE patients expressed higher levels of IL-18 receptor on their cell surface in response to tumor necrosis factor alpha (TNF alpha) or interferon-gamma stimulation. In response to IL-18 stimulation, these cells produced large amounts of TNF alpha. Of note, in the presence of IL-18, CLE keratinocytes failed to express IL-12. IL-12 has previously been shown to protect keratinocytes from ultraviolet irradiation-induced apoptosis. Keratinocytes from LE patients were more prone to die upon exposure to IL-18, and this increased apoptosis was abrogated by blockade of endogenously produced TNF alpha as well as by the addition of exogenous IL-12. IL-18 was highly expressed in biopsy samples of lesional skin from CLE patients. Conclusion. Our results demonstrate an intrinsic difference in the inflammatory response of keratinocytes and indicate an autocrine feedback loop involving TNF alpha(,) IL-18, and IL-12 family members. Our results suggest that IL-18 may occupy an important position in the cytokine hierarchy in CLE, indicating the potential benefit of a local agent that blocks IL-18 activity in the treatment of the manifestations of CLE.