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(American Journal of Pathology. 2005;167:27-37.)
© 2005 American Society for Investigative Pathology

Inhibition of Macrophage Nuclear Factor-B Leads to a Dominant Anti-Inflammatory Phenotype that Attenuates Glomerular Inflammation in Vivo

Heather M. Wilson^*, Salah Chettibi, Christian Jobin, David Walbaum^*, Andrew J. Rees^* and David C. Kluth^*

From the Department of Medicine and Therapeutics,^* University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, Scotland, United Kingdom; GE Healthcare, Bio-Sciences, Medical Diagnostics, London, United Kingdom; and the Department of Medicine, University of North Carolina, Chapel Hill, North Carolina

Infiltrating macrophages (m) 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-B in bone marrow-derived macrophages (BMDMs) by using a recombinant adenovirus expressing dominant-negative IB (Ad-IB). 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- synthesis was abrogated while interleukin-10 synthesis increased. In vivo, fluorescently labeled BMDMs transduced with Ad-IB 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-IB-transduced BMDMs to inhibit injury when activated by acute immune-mediated inflammation within the glomerulus.

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