Interferon‐alpha up‐regulates bcl‐2 expression and protects B‐CLL cells from apoptosis in vitro and in vivo

Abstract

The bcl-2 oncoprotein, which is involved in the t(14,18) translocation, protects cells against apoptosis. We examined the effects of interferon-alpha (IFN-alpha) on bcl-2 protein expression and apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. None of 12 patients with B-CLL examined expressed the t(14,18) translocation; however, all these, and seven other patients, expressed significant levels of bcl-2 protein. In vitro, IFN-alpha (500 U/ml over 18 h) increased bcl-2 expression on CLL cells (to 200 +/- 23% of control MCF, as determined by indirect immunofluorescence and flow cytometry, n = 10, P < 0.001). All of eight patients who received IFN-alpha (3 megaunits subcutaneously three times a week) demonstrated an increase in bcl-2 expression on circulating malignant cells. CLL cells undergo apoptotic cell death when cultured in vitro (35.6 +/- 10.3% DNA fragmentation after 18 h, n = 10). In the presence of IFN-alpha, however, DNA fragmentation was reduced to 6.6 +/- 5.8% (n = 10, P < 0.001). IFN-alpha also protected CLL cells against apoptosis induced by hydrocortisone and gamma irradiation (reducing DNA fragmentation from 63.9 +/- 12.6% to 10.8 +/- 4.5% and from 80 +/- 2.9% to 5.4 +/- 1.6%, respectively, P < 0.001 for both). The protective effect of IFN-alpha was dose dependent, and maintained for up to 24 h. Our data demonstrate that bcl-2 expression and apoptosis of CLL cells can be influenced by cytokines. In addition, it seems unlikely that the observed clinical responses to IFN-alpha in patients with CLL are due to a direct effect on the malignant cells.

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

“…56 Yet other nets involved in Type-I-IFN-induced cell-cycle arrest are believed to include the downregulation of the transcription factor MYC and the activation of mitogen-activated protein kinase (MAPK)14 or the adapter molecule CRK. 57,58 Contrasting experimental findings indicate that Type-I-IFNs can either induce tumor cell death 59 or protect cancer cells from chemical-induced apoptosis 60 (panels 2 and 5, Fig. 2).…”

Rescue by cytokines of apoptotic cell death induced by IL-2 deprivation of human antigen-specific T cell clones

“…STATs are central mediators of cytokine-induced transcriptional activation [42]. It has been shown that IFN-a/b induce, through activation of JAK family kinases, the tyrosine phosphorylation and nuclear translocation of STAT1 and STAT2 [24].…”

IL-4 and interferon gamma regulate expression of inducible nitric oxide synthase in chronic lymphocytic leukemia cells

“…[4][5][6][8][9][10][11][12][13][14][15] NGF is an autocrine survival factor for memory B cells. 41 We tested whether IL-2, IL-4, IL-6, IL-8, IFN-␣, IFN-␥, NGF or G-CSF would induce B-CLL cell NOS2 enzyme activity following in vitro culture.…”

“…3 A variety of factors prevent spontaneous apoptosis of cultured B-CLL cells; these include IL-2, IL-4, IL-6, IL-8, IFN-␣, IFN-␥, G-CSF, CD40 ligation, CD6 ligation and bone marrowderived stromal cells. [4][5][6][7][8][9][10][11][12][13][14][15][16] The lipid-soluble, gaseous free radical nitric oxide (NO) is an important regulator of apoptosis, and the viability of cultured B-CLL cells is dependent on the autocrine production of NO. 17 B-CLL cell apoptosis is regulated by caspases that promote apoptosis and by factors such as bcl-2 which inhibit apoptosis.…”