title: Acquisition of anergy to proinflammatory cytokines in nonimmune cells through endoplasmic reticulum stress response: a mechanism for subsidence of inflammation.
abstract: Acute endoplasmic reticulum (ER) stress causes induction of inflammatory molecules via activation of NF-kappaB. However, we found that, under ER stress conditions, renal mesangial cells acquire anergy to proinflammatory stimuli. Priming of the cells with ER stress inducers (tunicamycin, thapsigargin, A23187, and AB5 subtilase cytotoxin) caused blunted induction of MCP-1 in response to TNF-alpha, IL-1beta, macrophage-derived factors, or bystander macrophages. The magnitude of suppression was closely correlated with the level of GRP78, an endogenous indicator of ER stress. The suppression of MCP-1 under ER stress conditions was reversible and observed in general regardless of cell types or triggers of ER stress. The decrease in the level of MCP-1 mRNA was ascribed to transcriptional suppression via unexpected inhibition of NF-kappaB, but not to accelerated mRNA degradation. Subsequent experiments revealed that TNFR-associated factor 2, an essential component for TNF-alpha signaling, was down-regulated by ER stress. We also found that, under ER stress conditions, expression of NF-kappaB suppressor A20 was induced. Overexpression of A20 resulted in suppression of cytokine-triggered NF-kappaB activation and knockdown of A20 by RNA interference significantly attenuated induction of anergy by ER stress. In contrast, other ER stress-inducible/-related molecules that may suppress NF-kappaB (e.g., GRP78, NO, reactive oxygen species, and IkappaB) were not involved in the inhibitory effects of ER stress. These results elucidated ER stress-dependent mechanisms by which nonimmune cells acquire anergy to inflammatory stimuli under pathological situations. This self-defense machinery may play a role in halting progression of acute inflammation and in its spontaneous subsidence.
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Maro
authors.initials: M
authors.lastname: Okamura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Masanori
authors.initials: M
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D017635:Clonal Anergy / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D050527:Mesangial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects / Q000276:immunology; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D018836:Inflammation Mediators; D016328:NF-kappa B; D019284:Thapsigargin