c-Jun Is Required for Nuclear Factor-κB-Dependent, LPS-Stimulated Fos-Related Antigen-1 Transcription in Alveolar Macrophages.
Previously, we have reported that Fos-related antigen-1 (Fra-1) transcription factor promotes LPS-induced acute lung injury and mortality, and that LPS-induced Fra-1 expression in the lung occurs predominantly in alveolar macrophages. Nuclear factor-κB (NF-κB) and c-Jun transcription factors play key roles in modulating inflammatory and immune responses induced by infectious and non-infectious insults. Here, we report that NF-κB and c-Jun coregulate Fra-1 induction by LPS in alveolar macrophages and that this regulation occurs through both the NF-κB and the extracellular signal-regulated protein kinase (ERK) signaling pathways. Transient transfections with Fra-1 promoter-reporter constructs and inhibitor studies revealed that the transcriptional activation of Fra-1 by LPS in alveolar macrophages is mediated by NF-κB and ERK1/2 signaling. Importantly, chromatin immunoprecipitation assays revealed the recruitment of c-Jun and NF-κB to the endogenous Fra-1 promoter after LPS stimulation. We found that inhibition of ERK1/2 signaling reduced LPS-stimulated c-Jun and NF-κB recruitment to the promoter. Likewise, NF-κB inhibitor blocked LPS-induced NF-κB and c-Jun binding to the promoter. ERK1/2 inhibition had no effect on c-Jun activation but suppressed LPS-stimulated NF-κB phosphorylation. Finally, functional assays showed reduced levels of LPS-stimulated NF-κB regulated proinflammatory IL-1β and macrophage inflammatory protein-1α expression and increased antiinflammatory IL-10 expression in lung alveolar macrophages of Fra-1-null mice in vivo. Thus, our studies indicate that NF-κB and c-Jun coregulate LPS-induced Fra-1 transcription and that Fra-1 selectively modulates LPS-stimulated inflammatory cytokine expression in lung alveolar macrophages during inflammatory lung injury.
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
Rakesh K
RK
Mishra
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
Haranatha R
HR
Potteti
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
Chandramohan R
CR
Tamatam
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
Indira
I
Elangovan
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
Sekhar P
SP
Reddy
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D000099169:Fos-Related Antigen 1
D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D000099169:Fos-Related Antigen 1
Fos-related antigen-1; activator protein-1; inflammation; lung; macrophage