Inhibition of macrophage nuclear factor-kappaB leads to a dominant anti-inflammatory phenotype that attenuates glomerular inflammation in vivo.

Heather M Wilson, Salah Chettibi, C. Jobin, David Walbaum, Andrew Jackson Rees, D. C. Kluth

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Infiltrating macrophages (m phi) 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-KB in bone marrow-derived macrophages (BMDMs) by using a recombinant adenovirus; expressing dominant-negative IKB (Ad-IKB). 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-a synthesis was abrogated while interleukin-10 synthesis increased. In vivo, fluorescently labeled BMDMs transduced with Ad-IKB and injected into the renal artery significantly reduced inducible nitric oxide synthase and MHC class H 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-IKB-transduced BMDMs to inhibit injury when activated by acute immune-mediated inflammation within the glomerulus.

Original languageEnglish
Pages (from-to)27-37
Number of pages10
JournalAmerican Journal of Pathology
Volume167
Issue number1
Publication statusPublished - 2005

Keywords

  • INTRINSIC RENAL-CELLS
  • CRESCENTIC GLOMERULONEPHRITIS
  • IFN-GAMMA
  • IMMUNE-SYSTEM
  • GENE-TRANSFER
  • INJURY
  • EXPRESSION
  • ACTIVATION
  • ALPHA
  • CYTOKINES

Cite this

Inhibition of macrophage nuclear factor-kappaB leads to a dominant anti-inflammatory phenotype that attenuates glomerular inflammation in vivo. / Wilson, Heather M; Chettibi, Salah; Jobin, C.; Walbaum, David; Rees, Andrew Jackson; Kluth, D. C.

In: American Journal of Pathology, Vol. 167, No. 1, 2005, p. 27-37.

Research output: Contribution to journalArticle

Wilson, Heather M ; Chettibi, Salah ; Jobin, C. ; Walbaum, David ; Rees, Andrew Jackson ; Kluth, D. C. / Inhibition of macrophage nuclear factor-kappaB leads to a dominant anti-inflammatory phenotype that attenuates glomerular inflammation in vivo. In: American Journal of Pathology. 2005 ; Vol. 167, No. 1. pp. 27-37.
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