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* Department of Molecular Signaling and
Department of Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan; and
Organ Transplantation Unit, 1st Affiliated Hospital, China Medical University, Shenyang, China
Macrophage-mesangial cell interaction plays a crucial role in the pathogenesis of glomerulonephritis. Activated macrophages trigger mesangial cells to express an array of inflammation-associated genes via activation of NF-
B and AP-1. However, this inflammatory response is often transient and subsides spontaneously. We found that mesangial cells activated by bystander macrophages showed blunted responses of NF-
B to subsequent macrophage exposure. It was associated with sustained levels of I
B
, but not I
B
. The tolerance observed was reversible and reproduced by conditioned media from activated macrophages (macrophage-conditioned medium (M
CM)). In vivo priming of mesangial cells by activated glomerular macrophages also caused the tolerance of mesangial cells. The macrophage-derived tolerance inducers were heat-labile, and multiple molecules were involved. Among inflammatory cytokines produced by macrophages, TNF-
and IL-1
were able to induce mesangial cell tolerance dose-dependently. The mesangial cell tolerance was also observed in activation of the MAPK-AP-1 pathway; i.e., phosphorylation of ERK, JNK, and p38 MAPK by macrophages was blunted when the cells were pre-exposed to M
CM. Induction of c-fos and c-jun was also abrogated in mesangial cells pre-exposed to M
CM, and the suppression was attenuated by blockade of MAPK activation during the first exposure to M
CM. These data elucidated that mesangial cells, once exposed to macrophages, become insensitive to subsequent activation by macrophages and proinflammatory stimuli. This self defense of glomerular cells may play a role in the resolution of macrophage-mediated, acute glomerulonephritis.
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