Expression and release of chemokines associated with apoptotic cell death in human promonocytic U937 cells and peripheral blood mononuclear cells

To characterize mechanisms which may determine the fate of apoptotic cells, we investigated chemokine expression in apoptotic promonocytic U937 cells or peripheral blood mononuclear cells (PBMC). Exposure of U937 cells to eto poside (VP-16) or the nitric oxide (NO) donor DETA-NO, both inducers of apo ptosis in these cells, was associated with increased expression of the chem okines IL-8 and macrophage inflammatory protein-1 alpha. Up-regulation of I L-8 mRNA expression by VP-16 or DETA-NO was observed as early as 4 h or 6 h , respectively, after onset of treatment and was still detectable after 19 h of exposure. A serine protease inhibitor prevented both VP-16-induced apo ptosis and release of IL-8, whereas inhibition of p38 MAP kinases reduced I L-8 secretion only. Moreover, we observed that incubation with 2-chlorodeox yadenosine (CdA) up-regulated release of IL-8 from adherent PBMC in paralle l to induction of apoptosis. In these cells a modest but significant induct ion of TNF-alpha release by CdA was also detected. In addition, CdA augment ed release of IL-8 from whole blood cultures. By facilitating adequate recr uitment of phagocytes to sites of cell death, stress-induced up-regulation of chemokines associated with apoptosis may contribute to mechanisms aiming at efficient removal of apoptotic cells.