Progressive growth of human papillomavirus type 16-transformed keratinocytes is associated with an increased release of soluble tumour necrosis factor (TNF) receptor

Abstract

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...

Cell-Mediated Immune Response to Human Papillomavirus Infection

“…For example, Malejczyk and coauthors (85), comparing HPV-16-transformed cell sublines with different levels of tumorigenicity in nude (athymic) mice, showed a correlation between increased tumorigenicity, resistance to TNF-mediated inhibition of proliferation in vitro, and significantly decreased expression of TNF receptors. They also showed increased shedding of soluble type I TNF receptor in the more highly tumorigenic subline (83). Interestingly, levels of soluble type I and type II TNF receptors in serum have been shown to be significantly elevated in patients with HPV-16-or -18-associated cervical carcinomas or anogenital Bowen's carcinoma (87).…”

“…Using HLA-2.1 transgenic mice four immunogenic peptides were identified in vivo [E6 (29)(30)(31)(32)(33)(34)(35)(36)(37)(38), E7 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20), E7 (82)(83)(84)(85)(86)(87)(88)(89)(90), and E7 (86-93)]. In addition, CTL induction of PBMC from humans confirmed immunogenicity, in vitro, of three of the four peptides [E7 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20), E7 (82)(83)(84)(85)(86)(87)(88)(89)(90), and E7 (86-93)]. CTL to one of the...…”

<![CDATA[<B>Immune cellular response to HPV</B>: <B>current concepts</B>]]>

“…They have a strong antiviral and antitumoral action. TNF-α diminishes the expression of the E6/E7 genes in the cells infected by HPV 16 or 18 that have not yet been transformed; however, during tumoral progression, HPV-infected cells become insensitive to TNF-α [9].…”

“…Th1 cells produce Il-2, IFN-γ, and lymphotoxin; they promote cellular immunity, and are needed for effective responses in cases of intracellular pathogens (such as viruses) and for tumor cells. Th2 cells produce IL-4, IL-5, IL-6, and IL-10, and they favor humoral immunity against extracellular pathogens and allergic responses [9]. The regulation of the immune response is also controlled by cytokines produced by non-T-cells, known as type 1 and 2 cytokines.…”

“…Biological response modifiers and some cytokines have been isolated from cellular lineages from vulvar bowenoid papulosis. The regulation of cytokine liberation (especially TNF-α), and the response to its action among carcinogenic and non-carcinogenic (HPV 16+) cellular lineages, are indications of the role of local immunological vigilance in controlling tumoral progression [9]. In other words, the interaction of cytokines/chemokines liberated during humoral/cellular immune reaction is responsible for the regression, persistence, or progress of lesions associated with HPV.…”