Myeloid cells control termination of lung inflammation through the NF-kappaB pathway

Am J Physiol Lung Cell Mol Physiol. 2009 Mar;296(3):L320-7. doi: 10.1152/ajplung.90485.2008. Epub 2008 Dec 19.


Although acute lung inflammation in response to local or systemic infection involves myeloid and nonmyeloid cells, the interplay between different cell types remains poorly defined. Since NF-kappaB is a key transcription factor for innate immunity, we investigated whether dysregulated NF-kappaB activation in myeloid cells impacts inflammatory signaling in nonmyeloid cells and generation of neutrophilic lung inflammation in response to systemic endotoxemia. We generated bone marrow chimeras by fetal liver transplantation of cells deficient in IkappaBalpha or p50 into lethally irradiated NF-kappaB reporter transgenic mice. No differences were apparent between bone marrow chimeras in the absence of an inflammatory stimulus; however, following intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS), IkappaBalpha- or p50-deficient bone marrow chimeras showed increased NF-kappaB activation in nonhematopoietic cells, exaggerated neutrophilic inflammation, and higher mortality compared with untransplanted reporter mice and wild-type bone marrow chimeras. Primary bone marrow-derived macrophages (BMDM) from IkappaBalpha(-/-) or p50(-/-) exhibited increased NF-kappaB activation and macrophage inflammatory protein-2 production after LPS treatment compared with wild-type cells, and coculture of BMDM with lung epithelial (A549) cells resulted in increased NF-kappaB activation in A549 cells and excess IL-8 production by these epithelial cells. These studies indicate an important role for inhibitory members of the NF-kappaB family acting specifically within myeloid cells to limit inflammatory responses in the lungs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Chemokines, CXC / biosynthesis
  • Coculture Techniques
  • Female
  • Humans
  • I-kappa B Proteins / deficiency
  • I-kappa B Proteins / genetics
  • Lipopolysaccharides / toxicity
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism*
  • Myeloid Cells / pathology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / deficiency
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • NF-kappa B p50 Subunit / deficiency
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Pneumonia / immunology
  • Pneumonia / metabolism*
  • Pneumonia / pathology*
  • Transplantation Chimera


  • Chemokines, CXC
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • NF-KappaB Inhibitor alpha
  • Nfkb1 protein, mouse