1: J Biol Chem. 2001 Apr 27;276(17):13547-53. Epub 2001 Jan 19. 

Vanadate facilitates interferon alpha-mediated apoptosis that is dependent on
the Jak/Stat pathway.

Gamero AM, Larner AC.

Department of Immunology, Lerner Research Institute, The Cleveland Clinic
Foundation, Ohio 44195, USA.

Type I interferon (IFN)-dependent inhibition of cell growth can occur either in
the absence or presence of apoptosis. The mechanisms that determine whether or
not cells undergo apoptosis after exposure to IFN-alpha are not clear. This
study shows that a variety of cell lines that display growth inhibition but not
apoptosis in response to IFN-alpha will undergo programmed cell death when low
concentrations of the protein-tyrosine phosphatase inhibitor vanadate are added
with IFN-alpha. In contrast, the combination of tumor necrosis factor-alpha with
vanadate did not trigger apoptosis in these cells. Caspase-3 activity was
detected only in cells exposed to IFN-alpha and vanadate but not to IFN-alpha or
vanadate alone. The ability of IFN-alpha and vanadate to induce apoptosis did
not require expression of p53 and was blocked by N-acetyl-l-cysteine. Activation
of the Jak/Stat pathway and expression of IFN-inducible genes was not altered by
incubation of cells with IFN-alpha and vanadate compared with IFN-alpha alone.
However, mutant cells lacking Stat1, Stat2, Jak1, or Tyk2, or cells expressing
kinase inactive Jak1 or Tyk2 did not undergo apoptosis in the presence of
IFN-alpha and vanadate. These results suggest that IFN-alpha stimulation of
Stat-dependent genes is necessary, but not sufficient, for this cytokine to
induce apoptosis. Another signaling cascade that involves the activity of a
protein-tyrosine phosphatase and/or the generation of reactive oxygen species
may play an important role in promoting IFN-alpha-induced apoptosis.

PMID: 11278370 [PubMed - indexed for MEDLINE]


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2: Clin Exp Immunol. 1997 Jul;109(1):185-93. 

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

Kaneko S, Suzuki N, Koizumi H, Yamamoto S, Sakane T.

Department of Immunology, St. Marianna University School of Medicine, Kawasaki,
Kanagawa, Japan.

The control of cell survival and cell death is of central importance in tissues
with high cell turnover such as the lymphoid system. We have examined the effect
of cytokines on IL-2 deprivation-induced apoptosis of human antigen-specific T
helper clones with different cytokine production profiles. We found that IL-2,
interferon-alpha (IFN-alpha), and IFN-beta inhibited IL-2 deprivation apoptosis
in Th0, Th1, and Th2 clones. We also found that IL-2 protects T cell clones from
IL-2 deprivation apoptosis accompanying active proliferation and enhanced
expression of P53, Rb and Bcl-xL proteins. In contrast, IFN-alpha/beta rescued T
cell clones from apoptosis without active proliferation, and expression of
apoptosis-associated proteins tested so far was unaffected. This may be due to
the fact that T cells treated with IL-2 contained those located in S + G2/M
phases of the cell cycle, whereas the vast majority of T cells treated with
IFN-alpha/beta were located in G0/G1 phase. IFN-alpha/beta specifically induced
tyrosine phosphorylation and translocation into nucleus of signal transducers
and activators of transcription (STAT) 2 protein in the T cell clones. In
addition, over-expression of STAT2 by transfection of the cDNA prevented
apoptosis of the T cell clones. Our present study shows that IFN-alpha and -beta
mediate anti-apoptotic effect through other pathways than that of IL-2 in growth
factor deprivation apoptosis.

PMID: 9218843 [PubMed - indexed for MEDLINE]


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