Inhibition of macrophage nuclear factor-kappaB leads to a dominant anti-inflammatory phenotype that attenuates glomerular inflammation in vivo.
Infiltrating macrophages (mphi) can cause injury or facilitate repair, depending on how they are activated by the microenvironment. Studies in vitro have defined the roles of individual cytokines and signaling pathways in activation, but little is known about how macrophages integrate the multiple signals they receive in vivo. We inhibited nuclear factor-kappaB in bone marrow-derived macrophages (BMDMs) by using a recombinant adenovirus expressing dominant-negative IkappaB (Ad-IkappaB). This re-orientated macrophage activation so they became profoundly anti-inflammatory in settings where they would normally be classically activated. In vitro, the lipopolysaccharide-induced nitric oxide, interleukin-12, and tumor necrosis factor-alpha synthesis was abrogated while interleukin-10 synthesis increased. In vivo, fluorescently labeled BMDMs transduced with Ad-IkappaB and injected into the renal artery significantly reduced inducible nitric oxide synthase and MHC class II expression when activated naturally in glomeruli of rats with nephrotoxic nephritis. Furthermore, although they only comprised 15% of glomerular macrophages, their presence significantly reduced glomerular infiltration and activation of host macrophages. Injury in nephrotoxic nephritis was also decreased when assessed morphologically and by severity of albuminuria. The results demonstrate the power of Ad-IkappaB-transduced BMDMs to inhibit injury when activated by acute immune-mediated inflammation within the glomerulus.
Department of Medicine and Therapeutics, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, Scotland, AB25 2ZD, UK. h.m.wilson@abdn.ac.uk
Heather M
HM
Wilson
Salah
S
Chettibi
Christian
C
Jobin
David
D
Walbaum
Andrew J
AJ
Rees
David C
DC
Kluth
D000818:Animals; D001854:Bone Marrow Cells; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D016753:Interleukin-10 / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D009393:Nephritis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D010641:Phenotype; D051381:Rats; D014161:Transduction, Genetic
D016328:NF-kappa B; D016753:Interleukin-10