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Titolo:
MODULATION OF APO-1 FAS (CD95)-INDUCED PROGRAMMED CELL-DEATH IN MYELOMA CELLS BY INTERFERON-ALPHA(2)/
Autore:
EGLE A; VILLUNGER A; KOS M; BOCK G; GRUBER J; AUER B; GREIL R;
Indirizzi:
UNIV INNSBRUCK HOSP,DEPT INTERNAL MED,LAB MOL CYTOL,ANICHSTR 35 A-6020 INNSBRUCK AUSTRIA UNIV INNSBRUCK HOSP,DEPT INTERNAL MED,LAB MOL CYTOL A-6020 INNSBRUCK AUSTRIA INNSBRUCK UNIV,DEPT EXPT PATHOL A-6020 INNSBRUCK AUSTRIA INNSBRUCK UNIV,DEPT BIOCHEM A-6020 INNSBRUCK AUSTRIA
Titolo Testata:
European Journal of Immunology
fascicolo: 12, volume: 26, anno: 1996,
pagine: 3119 - 3126
SICI:
0014-2980(1996)26:12<3119:MOAF(P>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
TUMOR-NECROSIS-FACTOR; PROTEIN-KINASE-C; CHRONIC LYMPHOCYTIC-LEUKEMIA; FAS-INDUCED APOPTOSIS; HUMAN B-CELLS; MULTIPLE-MYELOMA; IN-VIVO; MONOCLONAL-ANTIBODY; MOLECULAR-CLONING; SURFACE ANTIGEN;
Keywords:
MYELOMA; INTERFERON ALPHA AND GAMMA; APO-1/FAS (CD95); INDUCED APOPTOSIS; PROTEIN KINASE C; MITOGEN-ACTIVATED PROTEIN KINASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
42
Recensione:
Indirizzi per estratti:
Citazione:
A. Egle et al., "MODULATION OF APO-1 FAS (CD95)-INDUCED PROGRAMMED CELL-DEATH IN MYELOMA CELLS BY INTERFERON-ALPHA(2)/", European Journal of Immunology, 26(12), 1996, pp. 3119-3126

Abstract

The Apo-1/Fas (CD95) antigen is known to be involved in the process of T cell-mediated target cell killing and has recently been shown to be expressed on myeloma cell lines and native malignant plasma cells. Several cytokines have been reported to interfere with spontaneous and even Apo-1/Fas-induced apoptosis, but no attempt has been made yet to investigate these interactions and the possible underlying mechanisms in myeloma cells. Since in myeloma patients Interferon (IFN)-alpha(2) displays a profound therapeutic effect in vivo, which is usually attributed to its growth inhibitory and/or immunomodulatory capacity, we set out to study the potential interference of IFN-alpha(2) with Apo-1/Fas-induced apoptosis. Contrary to expectations, IFN-alpha(2) reduced the degree of apoptosis caused by the treatment of five Apo-1/Fas-sensitive myeloma cell lines with a Fas monoclonal antibody (mAb). Simultaneous application of IFN-alpha(2) and Fas mAb was superior to the prolonged (i.e. > 8 h) preincubation with the cytokine as far as inhibitionof Apo-1/Fas-induced apoptosis was concerned. This effect of IFN-alpha(2) was neither explained by a down-regulation of the Apo-1/Fas receptor nor caused by modulation of the expression levels of c-myc, bcl-2-, bcl-x(L), bax- or p53 genes. IFN-alpha(2) did not alter the Apo-1/Fas-induced activity of Mitogen-activated protein kinase (MAPK) 1 and did not inhibit the Apo-1/Fas-mediated proteolytic cleavage of ADP-ribosyltransferase, a substrate of Interleukin-beta 1 converting enzyme (ICE) and homologues. However, activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) mimicked the effects of IFN-alpha(2). Furthermore, the bis-indolylmaleimide GF 109203X, a specific inhibitor of PKC, inhibited the effect of PMA as well as that of IFN-alpha(2) on Apo-1/Fas-induced apoptosis. These results point to a PKC-dependent mechanism of transient interaction between the intracellular signaling along the IFN-alpha(2) and the Apo-1/Fas pathway (downstream of MAPK signaling as well as of ICE homologues), which becomes exhausted by prolonged stimulation with the cytokine. According to our data IFN-alpha(2), applied continuously and in high doses resembling the therapeutic situation in vivo, inhibits myeloma growth. However, based on theobserved inhibitory effect of IFN-alpha(2) on Apo-1/Fas-induced apoptosis, a partial inhibition of the natural immune surveillance on myeloma cells by endoggenous IFN-alpha(2) present in the bone marrow microenvironment of this malignancy should be investigated.

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Documento generato il 26/05/20 alle ore 06:29:41