title: Ribosomal protein S19 is a novel therapeutic agent in inflammatory kidney disease.
abstract: RPS19 (ribosomal protein S19), a component of the 40S small ribosomal subunit, has recently been identified to bind the pro-inflammatory cytokine macrophage MIF (migration inhibitory factor). In vitro experiments identify RPS19 as the first endogenous MIF inhibitor by blocking the binding of MIF to its receptor CD74 and MIF functions on monocyte adherence to endothelial cells. In the present study, we sought to establish whether recombinant RPS19 can exert anti-inflammatory effects in a mouse model of anti-GBM (glomerular basement membrane) GN (glomerulonephritis) in which MIF is known to play an important role. Accelerated anti-GBM GN was induced in C57BL/6J mice by immunization with sheep IgG followed 5 days later by administration of sheep anti-mouse GBM serum. Groups of eight mice were treated once daily by intraperitoneal injection with 6 mg of RPS19/kg of body weight or an irrelevant control protein (human secretoglobin 2A1), or received no treatment, from day 0 until being killed on day 10. Mice that received control or no treatment developed severe crescentic anti-GBM disease on day 10 with increased serum creatinine, declined creatinine clearance and increased proteinuria. These changes were associated with up-regulation of MIF and its receptor CD74 activation of ERK (extracellular-signal-regulated kinase) and NF-κB (nuclear factor κB) signalling, prominent macrophage and T-cell infiltration, as well as up-regulation of Th1 [T-bet and IFNγ (interferon γ)] and Th17 [STAT3 (signal transducer and activator of transcription 3) and IL (interleukin)-17A] as well as IL-1β and TNFα (tumour necrosis factor α). In contrast, RPS19 treatment largely prevented the development of glomerular crescents and glomerular necrosis, and prevented renal dysfunction and proteinuria (all P<0.001). Of note, RPS19 blocked up-regulation of MIF and CD74 and inactivated ERK and NF-κB signalling, thereby inhibiting macrophage and T-cell infiltration, Th1 and Th17 responses and up-regulation of pro-inflammatory cytokines (all P<0.01). These results demonstrate that RPS19 is a potent anti-inflammatory agent, which appears to work primarily by inhibiting MIF signalling.
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.
authors.forename: Jun
authors.initials: J
authors.lastname: Lv
authors.forename: Xiao Ru
authors.initials: XR
authors.lastname: Huang
authors.forename: Jörg
authors.initials: J
authors.lastname: Klug
authors.forename: Suada
authors.initials: S
authors.lastname: Fröhlich
authors.forename: Philipp
authors.initials: P
authors.lastname: Lacher
authors.forename: Anping
authors.initials: A
authors.lastname: Xu
authors.forename: Andreas
authors.initials: A
authors.lastname: Meinhardt
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D050533:Glomerular Basement Membrane / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007371:Interferon-gamma; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D012269:Ribosomal Proteins / Q000627:therapeutic use*; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D012269:Ribosomal Proteins; C045084:invariant chain; C040343:ribosomal protein S19; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases