Progressive growth of human papillomavirus type 16-transformed keratinocytes is associated with an increased release of soluble tumour necrosis factor (TNF) receptor J Malejczyk"2, M Malejczyk23, F Breitburd3, S Majewski2'3, A Schwarz4, N Expert-Besanson5, S Jablonska3, G Orth2 and TA Luger4 Keywords: tumour necrosis factor; soluble tumour necrosis factor receptor; tumour cell growth; human papillomavirus Certain types of human papillomaviruses (HPVs) are known to be associated with intraepithelial neoplasia of the cervix and external genitalia (Jenson and Lancaster, 1990;Kiviat and Koutsky, 1993). These lesions usually display a slow, self-limited growth and frequently regress, either spontaneously or after treatment. However, some persisting lesions induced by 'high-risk' HPV types e.g. HPV 16, 18, 31 and 33, may evolve into invasive carcinomas (zur Hausen, 1989;Howley, 1991). The evidence accumulates that growth and dissemination of HPV-associated lesions are under control of local and/or systemic immune surveillance (Jablonska et Pfister, 1990). Especially, local production of immunoregulatory anti-tumour cytokines, e.g. TNF-a, IL-6 and TGF-f1, may play an important role. These cytokines were shown to be expressed by HPV-harbouring keratinocytes and may directly or indirectly affect growth of the transformed cells (Woodworth et al., 1990; Majewski et al., 1991;Malejczyk et al., 1991Malejczyk et al., , 1992. Accordingly, a non-tumorigenic SKv keratinocyte cell line established from vulvar intraepithelial neoplasia and harbouring and expressing integrated HPV16 DNA sequences (Schneider-Maunoury et al., 1987;1990) has been found to release TNF-a spontaneously which in turn exerted an autocrine growth inhibitory effect (Malejczyk et al., 1992). These results strongly suggest the existence of an autocrine TNF-amediated mechanism which could be, at least partially, responsible for self-limited growth and eradication of certain HPV-associated tumours.Progressive growth and dissemination of HPV-induced lesions may be, at least partially, related to escape from local cytokine-mediated surveillance. Indeed, highly tumorigenic HPV-harbouring epithelial cells have been found to be resistant to anti-proliferative activity of TGF-,B (Woodworth et al., 1990;Braun et al., 1990). Similarly, spontaneous tumorigenic progression of SKv cells was found to be associated with loss of susceptibility to autocrine TNFa-mediated growth limitation (Malejczyk et al., 1994). This phenomenon was, at least partially, related to a lowered type I TNF receptor (TNF-RI) expression, however, it could also depend on release of some TNF-cx inhibitory activity. Therefore, the aim of the present study was to investigate whether increased proliferation and tumorigenicity of SKv cells are associated with an ability to release TNF inhibitory factor(s). Materials and methods ReagentsRecombinant human TNF-a (rhTNF-a; specific activity 2 x 107 U mg-') was generously provided by BASF/Knoll (Ludwigshafen, Germany) and recombinant human TNF-,B (rhTNF-fl; sp...
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