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Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli¹

Kunihiro Hayakawa^*, Yiman Meng^*,, Nobuhiko Hiramatsu^*, Ayumi Kasai^*, Kozue Yamauchi^*,, Jian Yao^* and Masanori Kitamura^2,*

^* 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 IB, but not IB. The tolerance observed was reversible and reproduced by conditioned media from activated macrophages (macrophage-conditioned medium (MCM)). 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 MCM. Induction of c-fos and c-jun was also abrogated in mesangial cells pre-exposed to MCM, and the suppression was attenuated by blockade of MAPK activation during the first exposure to MCM. 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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