Increased Superoxide Anion Production and Glutathione Peroxidase Activity in Peritoneal Macrophages from Autoimmune-Prone MRL/Mp-lpr/lpr Mice

Abstract

We studied the release of superoxide anion (O₂^––) in peritoneal macrophages from autoimmune-prone MRL/Mp-lpr/lpr (MRL/l) mice. Compared to resident peritoneal macrophages from control MRL/ Mp- +/+ (MRL/n) mice, macrophages from MRL/l mice exhibited an age-related increase of spontaneous and PMA-induced O₂^–– secretion in association with the development of the autoimmune process. Analysis of the kinetic parameters of NADPH oxidase in macrophages revealed that MRL/l macrophages were in a primed state, as shown by the decreased K_m value of the oxidase for NADPH. Furthermore, we studied several key enzymes for their ability to scavenge the oxygen radicals in the macrophages. Among the enzymes studied, only glutathione peroxidase (GSH Px) activity was increased in peritoneal macrophages from MRL/l mice and this change was closely correlated with the increase in O₂^––; production. Thus, GSH Px activity in macrophages seems to play an important role in macrophage functions under increased oxidative stress.

Chemical induction of HO-1 suppresses lupus nephritis by reducing localiNOS expression and synthesis of anti-dsDNA antibody

“…Rokutan et al [42] showed increased oxygen intermediates in the organs from MRL/lpr mice, whereas reduced serum levels of antioxidants and radical scavengers have been reported in human SLE [43]. Treatment with antioxidants, such as vitamin E, suppressed circulating anti-dsDNA antibody levels and the development of renal disease [44,45].…”

“…Possible implications of superoxides in SLE have been demonstrated [42][43][44]. Rokutan et al [42] showed increased oxygen intermediates in the organs from MRL/lpr mice, whereas reduced serum levels of antioxidants and radical scavengers have been reported in human SLE [43].…”

Effects of n−3 and n−6 fatty acids on the activities and expression of hepatic antioxidant enzymes in autoimmune‐prone NZB×NZW F1 mice

“…The deleterious effects of oxidative stress have previously been associated with various pathological conditions (8--10), but the role of an impaired or defective antioxidant defense system in autoimmune diseases has been explored only to a limited extent (11)(12)(13). Our recent study on MRL/lpr mice indicated that along with other immunological abnormalities, these mice clearly showed a defective antioxidant defense system as the expression of hepatic antioxidant enzymes was significantly lower when compared to that of an MRL/+ strain (14).…”

An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity.

“…Other work has suggested a role for cells not of bone marrow origin in the development of 1pr lymphadenopathy (36)(37)(38) ensues, leading to lymphoid depletion and early mortality (39,40) . If, however, an lpr lymph node is also transplanted, these mice will develop adenopathy in that transplanted node (38), suggesting that nonhemopoietic cells may be necessary for full expression of the T cell defect .…”