MECHANISMS OF ACTION OF ANTIMALARIALS IN INFLAMMATION - INDUCTION OF APOPTOSIS IN HUMAN ENDOTHELIAL-CELLS

Antimalarials are beneficial therapeutic agents in systemic lupus and rheumatoid arthritis. These autoimmune diseases have abnormally low ap optosis of inflammatory cells. Both disorders have an abnormal angioge nesis. In the present report, antimalarials were demonstrated to selec tively increase apoptosis of HUVECs in vitro. A 24-h exposure to 50 or 150 mu M of the drugs was associated with a significant loss of subst rate-adherent cells. Chloroquine exhibited an inhibitory effect on HUV EC proliferation over 7 days. Programmed cell death in HUVECs rendered nonadherent by chloroquine was confirmed by the induction of DNA frag mentation in floating cells. Northern blot analysis revealed a rapidly increased expression of the bcl-x(s) gene without any change in the e xpression of the bcl-2 gene, indicating that HUVECs under chloroquine were undergoing apoptosis. The onset of the apoptotic cascade in HUVEC s appeared shortly after the addition of chloroquine. The effect of ch loroquine on apoptosis was distinct from acute cell lysis and was rest ricted to HUVECs. Antimalarials also induced IL-1 alpha production. In parallel, chloroquine alone did not increase the expression of IL-6. Anti-IL-1 alpha Ab or IL-1Ra only marginally reversed chloroquine-indu ced depression of proliferation for the low drug concentration, but no t the massive cell death effect at and above 50 mu M. Taken together, these data may indicate that antimalarials repress angiogenesis. The a utocrine mechanism involving IL-1 alpha accounts only for a minor frac tion of the full antiendothelial effect of chloroquine, which is mainl y dependent on apoptosis.