Polyamines and Immune Cells and Apoptosis

Polyamine-associated apoptosis in immune cells is an emerging area of investigation. Ferioli et al. (30) have demonstrated that modulation of polyamine oxidase activity by glucocorticoid administration to rats correlated with the level of apoptosis in the thymus and spleen. In a subsequent study, this group showed that mitoguazone, which inhibits spermidine and spermine synthesis by blocking S-adenosylmethionine decarboxylase, protected thymocytes from both spontaneous and etoposide-induced apoptosis; this protective effect was associated with a decrease in polyamine oxidase activity and total polyamine levels (31). In contrast, Jan et al. (32) reported that spontaneous and dexam-ethasone-induced apoptosis was inhibited by polyamines in rat thymocytes ex vivo.

In myelomonocytic HL-60 cells, etoposide-induced apoptosis correlated with polyamine efflux and decrease in polyamine content (33). In contrast, apoptosis in these cells induced by 2-deoxy-D-ribose was prevented by treatment with DFMO, and exogenously added polyamines restored apoptosis (34). The latter results were similar to those that we have observed in H. pylori-activated macrophages (35), as discussed in Subheading 4. Similarly, in HL-60 cells, spermine has been reported to trigger cytochrome c release from mitochondria, and initiate activation of caspase-3, causing cell death via apoptosis (36). These differences highlight the fact that the role of polyamines in apoptosis may vary depending on the nature of the death stimulus, as reported in IECs (7).

There is also substantial evidence that polyamines can be antiapoptotic in lymphocytes. Nitta et al. (37) found that in the murine WEHI23 B-cell line, induction of apoptosis by B-cell antigen receptor crosslinking was associated with decreased expression of polyamine biosynthetic enzymes, increased levels of polyamine catabolic enzymes, and decreased levels of intracellular polyamines. Addition of spermine repressed the apoptosis by inhibiting the loss of mitochondrial membrane depolarization (37). This same group used inhibitors of polyamine biosynthesis to examine the effect of polyamine depletion and showed that decreased intracellular polyamine levels induced apoptotic cell death in WEHI231 cells (38). Addition of exogenous polyamines reversed the observed features of apoptotic cell death. Similar effects were also observed in another human B-cell line, Ramos, and in a human T-cell line, Jurkat (38).

Penning et al. (16) have used rat/mouse T-cell hybridoma-derived PC60 R55/R75 cells to study TNF-a-induced apoptosis. TNF-a caused a transient increase in ODC activity followed by a decrease and a gradual depletion of the polyamine levels. A reduction of the intracellular spermine levels with the polyamine synthesis inhibitors mitoguazone or CGP48644a, or with Ms(ethyl)norspermine, potentiated the apoptosis caused by TNF-a, whereas addition of spermine reduced the apoptosis. Similar results were obtained in several other cell lines including CEM-CM3 human T-cells (16).

In conclusion, the published data in immune cells clearly show both pro- and anti-apoptotic effects of polyamines. These results appear to vary depending on the cell type, the nature of the stimulus, and the specific polyamines that are manipulated in these systems. Additionally, the role of polyamine oxidation may be of paramount importance, as illustrated in Subheading 4.

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