IKKβ en inflamación y tumorigénesis epitelial: análisis en ratones transgénicos

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 27-05-2008The skin constitutes the first barrier of protection against pathogens. It is a major target of toxic insults by physical and chemical agents. The epidermis must maintain a precise balance between cell proliferation, differentiation and cell loss by desquamation of corneocytes. Alterations in the control of cellular proliferation and differentiation or in the response to aggressions result in severe pathologies such as cutaneous neoplasias and inflammatory skin diseases. The physiological functions of the NF-κB transcription factor family are diverse, including immune responses, developmental processes, cell growth and modulation of apoptosis. NF-κB signaling is of great significance in epithelial homeostasis: in the skin, NF-κB activity is usually associated to decreased proliferation. The IKKβ subunit of the IKK complex plays an essential role in the activation of NF-κB in response to proinflammatory stimuli and IKKβ deficiency in skin leads to a severe inflammatory disease and hyperplasia of the epidermis. Different studies performed both in animal models and in human patients have revealed the implication of IKKβ in colon and mammary gland tumorigenesis. In this study we have generated a transgenic model overexpressing IKKβ in the basal layer of skin and other stratified epithelia; these transgenic mice carry a transgene directed by regulatory elements of the bovine keratin K5. Our results show that overexpression of IKKβ in keratinocytes leads to functional activation of the IKK/NF-κB signaling pathway. This activation results in an increase in the synthesis of several cytokines and inflammatory mediators, and finally in chronic inflammation in tissues with transgene expression. The inflammatory process is characterized by infiltration of macrophages and CD3+ T cells. Skin inflammation has histological features characteristic of several human diseases that result in dermo-epidermal dermatitis. Inflammation is associated with development of spontaneous tumor lesions in oral epithelia and dysplasia and malfunction in exocrine glands and teeth. By contrast, the skin is resistant to the development of spontaneous tumor lesions. Furthermore, IKKβ inhibits papilloma development in chemical skin carcinogenesis experiments. In summary, our results highlight the fundamental role of IKKβ in epithelial homeostasis and reveal the complex and divergent function of IKKβ in tumorigenesis in different stratified epithelia