Interleukin-15 (IL-15) is a potent inhibitor of several apoptosis pathways. One prominent path toward apoptosis is the ligand-induced association of TNF receptor 1 (TNFR1) with death domain adaptor proteins. Studying if and how IL-15 blocks TNFR1-mediated apoptosis in a murine fibroblast cell line (L929), we show here that IL-15 blocks TNFR1-induced apoptosis via IL-15Ralpha chain signaling. The intracellular tail of IL-15Ralpha shows sequence homologies to the TRAF2 binding motifs of CD30 and CD40. Most important, binding of IL-15 to IL-15Ralpha successfully competes with the TNFR1 complex for TRAF2 binding, which may impede assembly of key adaptor proteins to the TNFR1 complex, and induces IkappaBalpha phosphorylation. Thus, IL-15Ralpha chain stimulation is a powerful deflector of cell death very early in the apoptosis signaling cascade, while TNF-alpha and IL-15 surface as major opponents in apoptosis control.
The production and characterization of a monoclonal antibody (MoAb) designated Ber-H2, directed against a new epitope of the Ki-1 (CD30) antigen, are described. In comparison with the formerly reported Ki-1 MoAb whose reactivity with Hodgkin and Reed-Sternberg (H-RS) cells in frozen tissue sections is well-documented, the Ber-H2 MoAb showed new, important features: the labeling intensity of the Ber-H2 MoAb was much stronger, and the number of positively labeled cells was higher. Most important, however, was that the Ber-H2 MoAb could be applied in routinely processed, formaldehyde-fixed, paraffin-embedded tissue sections. Therefore, it was possible to investigate an unprecedented number of tumors received as frozen or formaldehyde-fixed material for expression of the CD30 antigen. Beside Hodgkin's disease, the Ber-H2 MoAb labeled a variable number of cells in lymphomatoid papulosis, peripheral T-cell lymphomas, and angoimmunoblastic lymphadenopathy. Among B-cell non-Hodgkin's lymphomas (NHLs), some cases containing large centroblast-like or immunoblast-like cells or displaying plasma- cellular differentiation were positive. This finding was in keeping with the reactivity of the Ber-H2 MoAb with activated B-cell blasts and a subpopulation of plasma cells in paraffin sections of normal lymphoid tissue. The diagnostic value of the Ber-H2 MoAb was most significant for a group of anaplastic large-cell (ALC) lymphomas (formerly frequently referred to as malignant histiocytosis or regressive atypical histiocytosis), of which more than 50 cases could be investigated, owing to applicability in paraffin sections. Although about one third of these ALC lymphomas did not express the leukocyte common (CD45) antigen, they were consistently reactive with the Ber-H2 MoAb in both frozen and paraffin-embedded tissue sections. Using the Ber-H2 MoAb, these Ki-1 lymphomas could be easily distinguished from other nonlymphoid anaplastic large-cell tumors.
An enzyme-linked immunosorbent assay (ELISA) has been developed that allows the quantitative determination of the Ki-1 (CD30) antigen in soluble form. Similar levels of sensitivity of this new Ki-1 ELISA and the ELISA previously described for measuring the soluble 55-kDa chain of the interleukin 2 receptor were seen. As assessed with this ELISA, the investigated Ki-1+ permanent cell lines released the Ki-1 antigen into the culture supernatant. In culture supernatants of concanavalin A-activated human peripheral blood lymphocytes, however, this antigen could not be detected. The released Ki-1 antigen has an apparent molecular weight (Mr) of 85,000, whereas the cell-associated Ki-1 antigen has an Mr of 105,000. We investigated sera from 30 normal donors, 15 patients with systemic infections, and 63 patients suffering from lymphomas for soluble Ki-1 antigen. In all sera from normal donors and patients with systemic infectious diseases, soluble Ki-1 antigen was below the detection limit (i.e., less than 70 pg). In contrast, high amounts of the soluble Ki-1 antigen were found in sera from 18 malignant lymphomas containing Ki-1+ tumor cells. This finding demonstrates that the release of the Ki-1 antigen takes place not only in vitro, but in vivo as well. Moreover, these results imply that the Ki-1 antigen may be used as a serum tumor marker.
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