EPIDERMAL SIGNAL-TRANSDUCTION AND TRANSCRIPTION FACTOR ACTIVATION IN ACTIVATED KERATINOCYTES

In the area of biology, many laboratories around the world are dissect ing and characterizing signal transduction mechanisms and transcriptio n factors responsive to various growth factors and cytokines, in vario us cell types. However, because of the differences in systems used, it is not clear whether these systems coexist, whether they interact mea ningfully, and what their relative roles are. Epidermal keratinocytes are the perfect cell type in which to integrate this knowledge, becaus e in these cells these mechanisms are known to be relevant. Keratinocy tes both produce and respond to growth factors and cytokines, especial ly in pathological conditions and during wound healing, when the physi ology of keratinocytes is altered in a way specified by the presence o f a subset growth factors and cytokines. In fact, growth factors and c ytokines cause the major changes in gene expression and keratinocyte b ehavior in various cutaneous diseases. In some cases, such as in wound healing, these responses are highly beneficial; in others, such as in psoriasis, they are pathological. It is not clear at present which ar e operating in which conditions, which are important for the healing p rocess and which are harmful. Growth factors and cytokines affect kera tinocytes sometimes simultaneously, at other times individually. In th is manuscript we describe the signal transduction pathways responsible for the effects of interferons, the EGF/TGF alpha family and the TNF alpha/IL-1 family of signaling molecules. We also describe the importa nt transcription factors known to be functional in epidermis, with par ticular emphasis on those factors that are activated by growth factors and cytokines. Finally, we describe what is known about transcription al regulation of keratin genes, especially those specifically expresse d in pathological processes in the epidermis. We expect that the enhan ced understanding of the pathways regulating gene expression in kerati nocytes will identify the pharmacological targets, the signal transduc ing proteins and the corresponding transcription factors, used by grow th factors and cytokines. This research will lead to development of co mpounds precisely aimed at those targets, allowing us to isolate and i nhibit the harmful side effects of growth factors and cytokines. Such compounds should lead to highly specific and therefore more effective treatments of the cutaneous disorders in which these pathways play sig nificant roles. (C) 1998 Elsevier Science Ireland Ltd. All rights rese rved.