PURINES AND CELL-DEATH

Increasing evidence suggests that adenosine and ATP not only modulate cell growth and differentiation, but may also act as inducers of cell death. In the session ''Purines and cell death,'' held during the Puri nes '96 Symposium and chaired by Claudio Franceschi (Modena, Italy) an d Geoffrey Burnstock (London, UK) presentation and discussion of new s tudies on the modulation of cell death by adenosine and ATP raised nov el implications for a possible role of purines in both development and in the pathophysiology of various diseases. The cloning of a new liga nd-gated P2X receptor (the P2X(7)) was reported, and pharmacological s tudies have demonstrated that this is the unique P-2Z receptor known t o cause cell death by cytolysis. During the session, induction of apop tosis by ATP was reported in a murine macrophage cell line (confirming a role for ATP in inflammation and immunomodulation), in cultures of renal mesangial cells and of endothelial cells from bovine main pulmon ary artery; furthermore, ATP was shown to modulate glutamate neurotoxi city in cerebellar granule cells, suggesting that apoptosis by ATP is not only restricted to cells of the immune lineage, but may represent a more general means to regulate cell survival. Adenosine and its deri vatives have been known for years to induce apoptosis of human lymphoi d tissues, but it has been demonstrated only recently that these effec ts can also occur in other cell types, and that they can be due either to the activation of extracellular adenosine receptors or to an intra cellular mechanism of action. During the session ''Purines and cell de ath,'' various authors reported apoptosis by adenosine analogues in hu man peripheral blood mononuclear cells, but also in chick sympathetic neurons, rat chromaffin cells, rat cerebellar granule neurons, intact chick embryos and rat microglial cells, suggesting that adenosine may play an important role not only in modulation of survival of lymphoid cells but also in the development and remodelling of the nervous syste m. A dual role for the adenosine A(3) receptor in cell survival was al so demonstrated in cells of the astroglial lineage, as shown by induct ion of apoptosis at high concentrations of A(3) receptor agonists and protection from spontaneous cell death at low concentrations, suggesti ng that this receptor may promote either cell death or survival likely depending on the metabolic and functional state of the tissue. It was also reported that, following an ischemic episode, an alterated metab olism of adenine nucleotides and nucleosides in the heart may be the b asis of the lack of recovery of phosphorylated forms of adenosine due to oxidative stress, therefore contributing to heart damage. Taken tog ether, all these data confirm the involvement of purines in modulation of cell survival in various organs and systems; moreover, based on th ese data, it is expected that the characterization of the specific pur inoceptor subtypes involved in these actions may lead to the developme nt of entirely new therapeutic approaches to several diseases. (C) 199 7 Wiley-Liss, Inc.