Anti-C-reactive protein inhibits cytoskeletal rearrangement without altering calcium influx in natural killer cell...

C-reactive protein (CRP), an acute phase protein in human serum, is present on large granular lymphocytes (LGL). Anti-CRP inhibits natural killer (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 early signal transduction events in NK activation. In the conjugates formed between LGL and targets (NK or ADCC), 75-90% of LGL respond with a calcium 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 calcium response of LGL. This was true for both NK and ADCC effector cells. Crosslinking anti-CRP with a secondary antibody did not alter this result. Next, the effect of PMA, a PKC activator, and calcium ionophore, A23187, on anti-CRP-mediated inhibition of cytotoxicity were studied. PMA alone reversed most of the inhibition of lysis seen with anti-CRP. Based on previous observations that anti-CRP inhibited target cell-stimulated release of lytic factors, the effect of anti-CRP on release of lytic factors stimulated by PMA and calcium ionophore was evaluated. 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 formed between effector and target cells, the polarization of cytoskeleton 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 exocytosis since anti-CRP inhibits the cytoskeletal polarization and the release of lytic factors and PMA might reverse anti-CRP-mediated inhibition by activating alternative mechanisms of cytotoxicity in effectors.