Disease-activated transcription factor: allergic reactions in human skin cause nuclear translocation of STAT-91 and induce synthesis of keratin K17.

Abstract

Epidermal keratinocytes have important immunologic functions, which is apparent during wound healing, in psoriasis, and in allergic and inflammatory reactions. In these processes, keratinocytes not only produce cytokines and growth factors that attract and affect lymphocytes but also respond to the polypeptide factors produced by the lymphocytes. Gamma interferon (IFN-y) is one such signaling polypeptide. Its primary molecular effect is activation of specific transcription factors that regulate gene expression in target cells. In this work, we present a molecular mechanism of lymphocyte-keratinocyte signaling in the epidermis. We have induced cutaneous delayed-type hypersensitivity reactions that are associated with an accumulation of lymphocytes. These resulted in activation and nuclear translocation of STAT-91, the IFN-,y-activated transcription factor, in keratinocytes in vivo and subsequent induction of transcription of keratin K17. Within the promoter of the K17 keratin gene, we have identified and characterized a site that confers the responsiveness to IFN--y and that binds the transcription factor STAT-91. Other keratin gene promoters tested were not induced by IFN-'y. These results characterize at the molecular level a signaling pathway produced by the infiltration of lymphocytes in skin and resulting in the specific alteration of gene expression in keratinocytes.The role of epidermal keratinocytes in defense against mechanical injury and desiccation has been appreciated for a long time, but their role in immunological defense became apparent only recently, when it was realized that keratinocytes can produce a cornucopia of growth factors, chemoattractants, and cytokines (reviewed in reference 24). Furthermore, keratinocytes express receptors for many polypeptide factors, respond to autocrine stimulation, and also respond to the signals produced by the immune system (30). The importance of signaling between keratinocytes and lymphocytes is apparent in the cutaneous disorders that involve both of these cell types, including delayed-type hypersensitivity (DTH), psoriasis, and atopic dermatitis (21,23,27).The most extensively studied signaling molecules of the immune system are the alpha, beta, and gamma interferons (IFN-a, IFN-1, and IFN--y), a subset of cytokines originally described as factors that protect cells from viral infections (reviewed in references 35 and 41). Certain diseases are thought to be associated with high levels of IFN-y in epidermis (27). Although the role of interferons in pathologic processes has not been clearly defined, they have been used recently in therapeutic trials for several dermatologic diseases, including those caused by viruses (12).IFN-a and IFN-P share a cell surface receptor, whereas IFN--y binds to a different receptor, and although their biological effects largely overlap, the effects of IFN-,y are distinct

Transcriptional Activation of Psoriasis‐Associated Cytokeratin K17 by Interferon‐γ

“…Whether K17 plays a causal role in the disease or whether the expression represents only a side effect of the underlying immunological disorder remains to be investigated. Nevertheless, the finding that induction of a delayed-type hypersensitivity reaction, a condition generating high local concentrations of IFN-y, leads to massive epidermal expression of K17 in vivo (Jiang et al, 1994; P. Kiehl and E. C. B., unpublished observation) underlines the potential importance of K17 expression in cutaneous inflammatory processes.…”

A Functional DNA Binding Domain Is Required for Growth Hormone-induced Nuclear Accumulation of Stat5B

“…2 Significant cell type-specific variability in the localization of other STATs has also been documented. For example, Stat1 prior to activation is mostly cytoplasmic in some cell types (7,14,42,43) but distributed throughout the nucleus and cytoplasm in other cells (5,6,8). Thus, individual STATs may possess localization properties that are regulated in a cell typedependent manner.…”

Inflammatory Versus Proliferative Processes in Epidermis

“…DNA Constructs-The plasmids containing keratin promoters and the control plasmids pRSVZ have been described previously (17,18,60). The plasmids containing the IL-8 promoter and (NFB)3-CAT were gifts from J. Vilcek (52); and those expressing NFB proteins were from A. Beg and D. Baltimore (35); those expressing C/EBP␤ were from S. Chen-Kiang (61); IB and His-NFB were from S. Ghosh (62,63), and CHOP was from D. Ron (64).…”

“…Our previous results have demonstrated that EGF or TGF␣, the proliferative signals, induce the expression of keratins K6b and K16 (17,18). Therefore, focusing on the K6b keratin, we decided to determine whether TNF␣, which is a strong proinflammatory but not a proliferative signal in keratinocytes (19), affects its expression.…”