DIFFERENTIAL REGULATION OF THE C3A AND C5A RECEPTORS (CD88) BY IFN-GAMMA AND PMA IN U937 CELLS AND RELATED MYELOBLASTIC CELL-LINES

We have analyzed the induction of the receptor for the anaphylatoxic p eptide C3a (C3aR) by the immunomodulator IFN-gamma, the phorbol ester PMA, and dibutyryl cAMP (Bt(2)cAMP) in comparison with the C5a recepto r (C5aR, CD88). For U937 cells. IFN-gamma and Bt(2)cAMP up-regulated t he C3aR to the same extent, whereas Bt(2)cAMP was 20-fold more effecti ve in C5aR induction. PMA increased the expression of the C5aR, and ac ted synergistically with IFN-gamma. In contrast, PMA did not increase specific I-125-hC3a binding, and actually antagonized C3aR induction b y IFN-gamma, Two related human cell lines of the myeloblastic/monocyti c lineage, HL-60 and Mono Mac 6, showed inducibility of the C3aR simil ar to U937 cells, The two receptors showed subtle differences in signa l transduction. Despite comparable numbers of both receptors, IFN-gamm a potentiated activation of the C5aR but not the C3aR, as measured by an increase in free cytosolic Ca2+ upon ligand activation, Interesting ly, Bt(2)cAMP-treatment led to a functional response to C3a in U937 ce lls. Such differences in receptor regulation and signaling might under lie the partly differing physiologic effects of C3a and C5a on, for ex ample, chemotaxis, induction of oxidative burst, or immunoregulatory f unctions.