Objective: To examine the role of immune complexes in the prostanoid metabolism of glomerular capillary endothelial cells (EC) and platelets in lupus nephritis. Heat aggregated IgG (HA-IgG), instead of immune complexes, was incubated using an in vitro coculture system with human umbilical vein EC, instead of glomerular capillary EC, and platelets. The effect of complement component C1q and a novel imidazole-type thromboxane A2 (TXA2) synthetase inhibitor, DP-1904, on this prostanoid metabolism change was also investigated.
Methods: EC monolayers (1.5x10(5) cells/well) were incubated with various concentrations of HA-IgG, monomeric IgG, or medium alone for 1 h at 37 degrees C, and then incubated with platelet suspensions (1x10(8) cells/ml) for various times. Concentrations of TXB2 and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), the stable hydrolysis products of TXA2 and prostaglandin I2 (PGI2), respectively, released in the supernatants were measured by ELISA.
Results: HA-IgG bound to EC monolayers produced TXB2 and 6-keto-PGF(1alpha) in a concentration dependent manner and much more than monomeric IgG or medium alone did. However, the production of 6-keto-PGF(1alpha) stimulated with HA-IgG was much lower than that of TXB2, indicating a large imbalance between TXA2 and PGI2. Preincubation of HA-IgG with purified C1q partially suppressed the production of TXB2, but not that of 6-keto-PGF(1alpha). DP-1904 suppressed the production of TXB2 completely, but by sharp contrast, it dramatically increased the production of 6-keto-PGF(1alpha) from EC and platelets by HA-IgG.
Conclusion: The large imbalance of TXA2 and PGI2 produced by the interaction of EC, immune complexes, and platelets may be associated with alterations in glomerular pathological findings and hemodynamics mediated by immune complexes in lupus nephritis. C1q and a TXA2 synthetase inhibitor may improve the abnormal prostanoid metabolism change of lupus nephritis.