Reversal of Established Rat Crescentic Glomerulonephritis by Blockade of Macrophage Migration Inhibitory Factor (MIF): Potential Role of MIF in Regulating Glucocorticoid Production

Abstract

Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine that also counter-regulates glucocorticoid action. We investigated whether immunoneutralization of MIF could reverse established experimental crescentic glomerulonephritis and if this treatment could modulate endogenous glucocorticoid levels. Accelerated anti-GBM glomerulonephritis was induced in six littermate pairs of rats. Once crescentic disease was established on day 7, one animal in each pair was given a daily injection of neutralizing anti-MIF antibody (Ab) or irrelevant isotype control Ab for 14 days and then killed on day 21. In addition, a group of 6 animals was killed on day 7 of disease without any treatment. Animals receiving the control Ab exhibited a rapidly progressive glomerulonephritis with severe renal injury (proteinuria), loss of renal function (creatinine clearance), anemia, and marked histologic damage (including glomerular crescent formation), compared with animals killed on day 7 without treatment. In contrast, anti-MIF Ab treatment partially reversed the disease by restoring normal renal function and reducing histological damage compared with untreated animals killed on day 7 (p < 0.05). Interestingly, anti-MIF Ab treatment also prevented severe anemia (p < 0.05). Reversal of disease was associated with a significant reduction in leukocyte infiltration and activation and renal interleukin-1 (IL-1) production. Importantly, anti-MIF Ab treatment caused a significant increase in endogenous serum corticosterone levels, which correlated with the reversal of disease parameters. In conclusion, this study has demonstrated that blocking MIF activity can partially reverse established crescentic glomerulonephritis and suggests that MIF operates by both enhancing the cellular immune response and suppressing the endogenous anti-inflammatory glucocorticoid response.

Macrophage migratory inhibitory factor (MIF) expression in acute graft-versus-host disease (GVHD) in allogeneic hemopoietic stem cell transplant recipients

“…9 The ability of anti-MIF antibody to protect against the lethality of endotoxemia and to inhibit the induction of renal injury in rat crescentic glomerulonephritis further supports that MIF action is pro-inflammatory. 8,9,[23][24][25][26][27] Taken together, our findings suggest that MIF also may be one of the important mediators involved in the pathogenesis of aGVHD.…”

Smad7 Gene Therapy Ameliorates an Autoimmune Crescentic Glomerulonephritis in Mice

“…In past decades, many studies have shown that deletion of T cells as well as macrophages attenuates crescentic glomerulonephritis (23,25,34), demonstrating an essential role for T cells and macrophages in the pathogenesis of crescentic glomerulonephritis. In addition, NF-B-dependent proinflammatory cytokines, including IL-1 and TNF-␣, have been shown to play a critical role in the pathogenesis of crescentic glomerulonephritis (35,36). Blockade of NF-B inhibits crescentic glomerulonephritis in a rat model of anti- glomerular basement membrane disease, demonstrating a critical role for the NF-B pathway in progressive renal injury (37).…”

A Role for Macrophage Migration Inhibitory Factor in the Neonatal Respiratory Distress Syndrome

“…In rats, mice and nonhuman primates, free corticosteroid levels increase substantially in late gestation (24), and corticosteroid receptor expression rises sharply at E18.5 in fetal mouse lung (40). MIF is known to regulate the anti-inflammatory and immunosuppressive properties of glucocorticoids (17,35,(41)(42)(43)(44) and may influence glucocorticoid production during systemic inflammation (45). Glucocorticoids in low concentrations also have been shown to induce MIF secretion (41), which then exerts an autocrine/paracrine effect on glucocorticoid action (41,43,44).…”