ANTI-C-REACTIVE PROTEIN INHIBITS CYTOSKELETAL REARRANGEMENT WITHOUT ALTERING CALCIUM INFLUX IN NATURAL-KILLER-CELL ACTIVATION

C-reactive protein (CRP), an acute phase protein in human serum, is pr esent on large granular lymphocytes (LGL). Anti-CRP inhibits natural k iller (NK) cell-mediated lysis. Our current study shows that anti-CRP also inhibits antibody-dependent cell-mediated cytotoxicity (ADCC) of LGL. Calcium influx and protein kinase C (PKC) activation are the earl y signal transduction events in NK activation. In the conjugates forme d between LGL and targets (NK or ADCC), 75-90% of LGL respond with a c alcium influx. Addition of anti-CRP had no effect on the percentage of LGL which respond to target cell binding or on the magnitude of the c alcium response of LGL. This was true for both NK and ADCC effector ce lls. Crosslinking anti-CRP with a secondary antibody did not alter thi s result. Next, the effect of PMA, a PKC activator, and calcium ionoph ore, A23187, on anti-CRP-mediated inhibition of cytotoxicity were stud ied. PMA alone reversed most of the inhibition of lysis seen with anti -CRP. Based on previous observations that anti-CRP inhibited target ce ll-stimulated release of lytic factors, the effect of anti-CRP on rele ase of lytic factors stimulated by PMA and calcium ionophore was evalu ated. Anti-CRP blocked the release of lytic factors stimulated by PMA and ionophore. Release of lytic factors involves the rearrangement of cytoskeletal element of NK cell toward the target cell. The effect of anti-CRP on cytoskeletal reorganization was studied. In conjugates for med between effector and target cells, the polarization of cytoskeleto n at the contact site of NK and target cell was significantly reduced in the presence of anti-CRP. Although anti-CRP inhibits both ADCC and NK lytic mechanisms, it does not alter target cell-induced Ca2+ influx . CRP interacts with the secretory mechanisms involved in granule exoc ytosis since anti-CRP inhibits the cytoskeletal polarization and the r elease of lytic factors and PMA might reverse anti-CRP-mediated inhibi tion by activating alternative mechanisms of cytotoxicity in effecters . (C) 1994 Academic Press, Inc.