Keratins and the Keratinocyte Activation Cycle
2001; Elsevier BV; Volume: 116; Issue: 5 Linguagem: Inglês
10.1046/j.1523-1747.2001.01327.x
ISSN1523-1747
AutoresIrwin M. Freedberg, Marjana Tomic‐Canic, Mayumi Komine, Miroslav Blumenberg,
Tópico(s)Protein Kinase Regulation and GTPase Signaling
ResumoIn wound healing and many pathologic conditions, keratinocytes become activated: they turn into migratory, hyperproliferative cells that produce and secrete extracellular matrix components and signaling polypeptides. At the same time, their cytoskeleton is also altered by the production of specific keratin proteins. These changes are orchestrated by growth factors, chemokines, and cytokines produced by keratinocytes and other cutaneous cell types. The responding intracellular signaling pathways activate transcription factors that regulate expression of keratin genes. Analysis of these processes led us to propose the existence of a keratinocyte activation cycle, in which the cells first become activated by the release of IL-1. Subsequently, they maintain the activated state by autocrine production of proinflammatory and proliferative signals. Keratins K6 and K16 are markers of the active state. Signals from the lymphocytes, in the form of Interferon-γ, induce the expression of K17 and make keratinocytes contractile. This enables the keratinocytes to shrink the provisional fibronectin-rich basement membrane. Signals from the fibroblasts, in the form of TGF-β, induce the expression of K5 and K14, revert the keratinocytes to the healthy basal phenotype, and thus complete the activation cycle. In wound healing and many pathologic conditions, keratinocytes become activated: they turn into migratory, hyperproliferative cells that produce and secrete extracellular matrix components and signaling polypeptides. At the same time, their cytoskeleton is also altered by the production of specific keratin proteins. These changes are orchestrated by growth factors, chemokines, and cytokines produced by keratinocytes and other cutaneous cell types. The responding intracellular signaling pathways activate transcription factors that regulate expression of keratin genes. Analysis of these processes led us to propose the existence of a keratinocyte activation cycle, in which the cells first become activated by the release of IL-1. Subsequently, they maintain the activated state by autocrine production of proinflammatory and proliferative signals. Keratins K6 and K16 are markers of the active state. Signals from the lymphocytes, in the form of Interferon-γ, induce the expression of K17 and make keratinocytes contractile. This enables the keratinocytes to shrink the provisional fibronectin-rich basement membrane. Signals from the fibroblasts, in the form of TGF-β, induce the expression of K5 and K14, revert the keratinocytes to the healthy basal phenotype, and thus complete the activation cycle. extracellularly regulated kinase IkB kinase IL-1 receptor associated kinase Janus activated kinase mitogen activated protein kinase MAPK/ERK kinase NFkB inducing kinase protein kinase-C TRAF associated kinase TNFα receptor associated death domain TNFα receptor associated factor Epidermal keratinocytes have two alternative pathways open to them: differentiation and activation. In healthy epidermis, keratinocytes differentiate from the basal layer through squamous, granular, and cornified layers. This process has been described in several review articles recently (Eckert et al., 1997Eckert R.L. Crish J.F. Robinson N.A. 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From the perspective of this paper, we point out that the differentiation process can be affected by vitamins, such as retinoic acid and vitamin D3, and that the expressions of specific keratin genes have been often used as markers for basal versus differentiating cells: K5 and K14 are expressed in the basal layer, K1, K2, and K10 in the differentiating cells (reviewed inSchweizer, 1993Schweizer J. Murine epidermal keratins.in: Darmon M. Blumenberg M. Molecular Biology of the Skin: the Keratinocyte. Academic Press, New York1993: 33-72Crossref Google Scholar). In response to epidermal injury, however, or in certain pathologic conditions such as psoriasis, an alternative pathway is open to keratinocytes, that of activation (reviewed inBarker et al., 1991Barker J.N. Mitra R.S. Griffiths C.E. Dixit V.M. Nickoloff B.J. Keratinocytes as initiators of inflammation.Lancet. 1991; 337: 211-214Abstract PubMed Scopus (446) Google Scholar;Nickoloff and Turka, 1993Nickoloff B.J. Turka L.A. 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The activation process can be affected by growth factors and cytokines, such as interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), transforming growth factor α (TGF-α), TGF-β, and interferon-γ (IFN-γ). The expression of specific keratin genes has been used as a marker for activated cells; characteristically, activated keratinocytes express K6, K16, and K17 keratin proteins, distinct from the keratins of the healthy epidermis. Activated keratinocytes are hyperproliferative, migratory, change their cytoskeleton, augment the levels of cell surface receptors, and produce components of the basement membrane. These responses are essential for re-epithelialization of the injured area. Activated keratinocytes also produce paracrine signals to alert fibroblasts, endothelial cells, melanocytes, and lymphocytes, as well as autocrine signals targeted at neighboring keratinocytes. These responses are essential for orchestrating the actions of the surrounding cell types in repair of the injured tissue. The affected cell types, in turn, produce their own autocrine and paracrine signals, which modify the actions of activated keratinocytes. Eventually, having responded to the injury, keratinocytes receive a “de-activation” signal and revert to the normal differentiation pathway. The regulatory processes involved in keratinocyte activation and de-activation, as well as the concomitant changes in keratin gene expression, are coordinated by secreted growth factors and cytokines, produced both by the keratinocytes and by the surrounding cell types. These regulatory processes are the subject of this review. In healthy epidermis, keratinocytes are not activated and they slowly proliferate in the basal layer and differentiate in the suprabasal layers. Being exposed to the surroundings, however, they must be prepared to respond very quickly to injury from the environment. 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Recently, we reported on the mechanism of induction of K6 by IL-1 (Komine et al, 2001). Skin biopsies in organ culture treated with IL-1 express K6 throughout the tissue. In cultures only confluent keratinocytes respond to IL-1; subconfluent cultures do not. Using DNA-mediated cell transfection, we identified the IL-1 responsive DNA element in the K6 promoter, and determined that it contains a complex of C/EBP binding sites. Thus, IL-1 initiates keratinocyte activation not only by triggering additional signaling events, but also by inducing directly the synthesis of K6 in epidermal keratinocytes, and thus changing the composition of their cytoskeleton. Whereas IL-1 initiates the keratinocyte activation, other signals are used to maintain keratinocyte activation. Such signals need not be already present in healthy tissue and can have overlapping but different mechanisms of action from IL-1. Because these signals are not present in healthy tissue, keratinocytes do not need to elaborate sophisticated hair-trigger mechanisms to respond to or protect themselves from these signals. One such signal is TNF-α. Induced by IL-1, TNF-α can maintain keratinocytes in an activated state (Nickoloff and Turka, 1993Nickoloff B.J. Turka L.A. Keratinocytes key immunocytes of the integument.Am J Pathol. 1993; 143: 325-331PubMed Google Scholar). TNF-α was discovered from two independent lines of research, first as an inducer of necrosis in some tumor cells and second as a cause of cachexia in septic animals. Subsequently, it was established that TNF-α is one of the proinflammatory cytokines that induce many inflammatory effects, such as fever and sho
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