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

Han W, Joo M, Everhart MB, Christman JW, Yull FE, Blackwell TS. Myeloid cells control termination of lung inflammation through the NF-kappa B pathway. Am J Physiol Lung Cell Mol Physiol 296: L320-L327, 2009. First published December 19, 2008; doi: 10.1152/ajplung.90485.2008.-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-kappa B is a key transcription factor for innate immunity, we investigated whether dysregulated NF-kappa B 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 I kappa B alpha or p50 into lethally irradiated NF-kappa B 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), I kappa B alpha- or p50-deficient bone marrow chimeras showed increased NF-kappa B 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 I kappa B alpha(-/-) or p50(-/-) exhibited increased NF-kappa B 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-kappa B 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-kappa B family acting specifically within myeloid cells to limit inflammatory responses in the lungs.