Inhibition of mesangial cell nitric oxide in MRL/lpr mice by prostaglandinJ(2) and proliferator activation receptor-gamma agonists

MRL/Mp-lpr/lpr (MRL/lpr) mice develop immune complex glomerulonephritis sim ilar to human lupus, Glomerular mesangial cells are key modulators of the i nflammatory response in lupus nephritis, When activated, these cells secret e inflammatory mediators including NO and products of cyclooxygenase perpet uating the local inflammatory response. P6J(2), a product of cyclooxygenase , is a potent in vitro inhibitor of macrophage inflammatory functions and i s postulated to function as an in vivo inhibitor of macrophage-mediated inf lammatory responses, We hypothesized that in lupus, a defect in PGJ(2), pro duction allows the inflammatory response to continue unchecked. To test thi s hypothesis, mesangial cells were isolated from MRL/lpr and BALB/c mice an d stimulated with IL-1 beta or LPS plus IFN-gamma, In contrast to the 2.- t o 3-fold increase in PGJ(2) production by stimulated BALB/c mesangial cells , supernatant PGJ(2) did not increase in MRL/lpr mesangial cell cultures. N O production in stimulated MRL/lpr and BALB/c mesangial cells, was blocked by PGJ(2) and pioglitazone, These studies suggest that abnormalities in PGJ (2) production are present in MRL/lpr mice and may be linked to the heighte ned activation state of mesangial cells in these mice.