Contact of blood with foreign surfaces, specifically dialysis membranes, causes cell activation which has widely been assumed to be mediated by complement (C). To explore the possibility of C-independent activation, we examined different cell types: PMN, human monocytes and the cell lines U937 or HL60, washed human platelets and rat glomerular epithelial cell (primary) cultures (GEC), under serum-free conditions and after addition of anti-C3 F(ab)2, respectively. The monitored biological effects were release of PGE2, TXB2 or interleukin 1 and generation of O2- radicals. To further explore the mechanisms involved, phospholipid metabolism was studied by measuring IP3 and DG (14C-arachidonic or oleic acid prelabeled U937 and HL60 cells); changes of cytosolic Ca++ (Quin2 technique) were also determined. The results show that in absence of C, brief (2 min) contact with cuprammonium (CU) stimulated: (a) PGE2 release in U937 and human monocytes or GEC; (b) TXB2 release in washed platelets; (c) slow interleukin 1 release by monocytes; and (d) generation of O2- radicals in PMN. Artifacts due to endotoxin were excluded by appropriate polymyxin control experiments and by comparison of effects with those of bacterial LPS. Potential synthesis of C3 by U937 was excluded by addition of anti-C3 F(ab)2. C-independent cell activation was accompanied by increase of DG, but not IP3 (suggesting involvement of protein C kinase dependent mechanisms) and by increased cytosolic Ca++. To further explore the initial signal involved, incubations were carried out with covalently modified CU members (DEAE cellulose) and in the presence of mM concentrations of monosaccharides. Cationic modification of CU membranes reduced C-independent cell activation.(ABSTRACT TRUNCATED AT 250 WORDS)