Nitric oxide/platelet activating factor cross-talk in mesangial cells modulates the interaction with leukocytes

Platelet activating factor (PAF) and nitric oxide (NO) exert opposite effects on adherence and activation of circulating leukocytes to endothelium. Several studies have implicated the production of PAF and NO by mesangial cells in the regulation of glomerular filtration, permeability and inflammation. However, the reciprocal interaction between PAF and NO in mesangial cells and their role in leukocyte adhesion has not been investigated.

We evaluated whether blockade of constitutive production of NO by two different NO synthase (NOS) inhibitors (L-NAME and L-NMMA) could modulate PAF synthesis, and conversely whether exogenous PAF could influence the production of NO by mesangial cells. We evaluated whether modulation of PAF synthesis by NOS inhibitors could affect leukocyte adhesion to mesangial cells. The effect of PAF-receptor antagonist WEB2170, of anti-beta(2) integrins and intracellular adhesion molecule-1 (ICAM-1) blocking antibodies and of soluble Sialyl-Lewis-a also was evaluated.

Blockade of NO synthesis by NOS inhibitors induced a spontaneous synthesis of PAF that was conversely inhibited by NO generation. On the other hand, PAF inhibited both the basal and l-arginine induced synthesis of NO by mesangial cells. Moreover, NOS inhibition promoted the adhesion of polymorphonuclear cells and monocytes to mesangial cells by a mechanism dependent on the synthesis of PAF and on the interaction of beta(2) integrins and ICAM-1.

These data indicate that PAF and NO exhibit a bi-directional effect on their respective synthesis in human mesangial cells, and suggest that their reciprocal regulation may be relevant for leukocyte adhesion to glomerular mesangial cells.