RESUMEN
The type I interferons, interferon-alpha (IFN-alpha) and interferon-beta (IFN-beta), are situated on the short arm of chromosome 9, specifically 9p21-22. This locus lies very close to an area that is deleted or rearranged in nearly half of all melanomas tested. The identification of 9p rearrangements in both melanoma precursor lesions (dysplastic naevi) and primary lesions has implicated the 9p locus in the early stages of melanoma development. Recent evidence has demonstrated that metastatic melanoma cell lines have a specific loss of IFN-alpha gene expression, a defect that appears to occur at the level of transcription. In this study, we examined the expression of IFN-alpha in cell lines isolated from the various stages of melanoma progression, with a view to determine the prevalence of the IFN-alpha transcription defects exhibited by malignant melanoma, and to assess whether the loss of IFN-alpha expression was particular to a certain stage of melanoma progression. We showed that all the melanoma cell lines tested (n=20) demonstrated an inability to express IFN-alpha, a defect that was reflected in the apparent inactivity of the IFN-alpha promoter. These defects were found to occur in cells isolated from early melanomas, lending support to the hypothesis that IFN-alpha has a role in the aetiology of malignant melanoma.
Asunto(s)
Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Interferón-alfa/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Transcripción Genética , Antineoplásicos/metabolismo , Línea Celular Tumoral , Cromosomas Humanos Par 9 , Proteínas de Unión al ADN , Ensayo de Inmunoadsorción Enzimática , Genes Supresores de Tumor , Humanos , Interferón-alfa/metabolismo , Melanocitos , Reacción en Cadena de la Polimerasa , Prevalencia , Regiones Promotoras Genéticas/fisiología , ARN Mensajero/metabolismo , ARN Neoplásico/metabolismo , Virus Sendai , TransfecciónRESUMEN
We have generated mice null for IFN-beta and report the diverse consequences of IFN-beta for both the innate and adaptive arms of immunity. Despite no abnormalities in the proportional balance of CD4 and CD8 T cell populations in the peripheral blood, thymus, and spleen of IFN-beta-/- mice, activated lymph node and splenic T lymphocytes exhibit enhanced T cell proliferation and decreased tumor necrosis factor alpha production, relative to IFN-beta+/+ mice. Notably, constitutive and induced expression of tumor necrosis factor alpha is reduced in the spleen and bone marrow (BM) macrophages, respectively, of IFN-beta-/- mice. We also observe an altered splenic architecture in IFN-beta-/- mice and a reduction in resident macrophages. We identify a potential defect in B cell maturation in IFN-beta-/- mice, associated with a decrease in B220+ve/high/CD43-ve BM-derived cells and a reduction in BP-1, IgM, and CD23 expression. Circulating IgM-, Mac-1-, and Gr-1-positive cells are also substantially decreased in IFN-beta-/- mice. The decrease in the numbers of circulating macrophages and granulocytes likely reflects defective maturation of primitive BM hematopoiesis in mice, shown by the reduction of colony-forming units, granulocyte-macrophage. We proceeded to evaluate the in vivo growth of malignant cells in the IFN-beta-/- background and give evidence that Lewis lung carcinoma-specific tumor growth is more aggressive in IFN-beta-/- mice. Taken altogether, our data suggest that, in addition to the direct growth-inhibitory effects on tumor cells, IFN-beta is required during different stages of maturation in the development of the immune system.