| First Author | Mishra RK | Year | 2016 |
| Journal | Am J Respir Cell Mol Biol | Volume | 55 |
| Issue | 5 | Pages | 667-674 |
| PubMed ID | 27286066 | Mgi Jnum | J:251165 |
| Mgi Id | MGI:6101322 | Doi | 10.1165/rcmb.2016-0028OC |
| Citation | Mishra RK, et al. (2016) c-Jun Is Required for Nuclear Factor-kappaB-Dependent, LPS-Stimulated Fos-Related Antigen-1 Transcription in Alveolar Macrophages. Am J Respir Cell Mol Biol 55(5):667-674 |
| abstractText | 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-kappaB (NF-kappaB) 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-kappaB and c-Jun coregulate Fra-1 induction by LPS in alveolar macrophages and that this regulation occurs through both the NF-kappaB 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-kappaB and ERK1/2 signaling. Importantly, chromatin immunoprecipitation assays revealed the recruitment of c-Jun and NF-kappaB to the endogenous Fra-1 promoter after LPS stimulation. We found that inhibition of ERK1/2 signaling reduced LPS-stimulated c-Jun and NF-kappaB recruitment to the promoter. Likewise, NF-kappaB inhibitor blocked LPS-induced NF-kappaB and c-Jun binding to the promoter. ERK1/2 inhibition had no effect on c-Jun activation but suppressed LPS-stimulated NF-kappaB phosphorylation. Finally, functional assays showed reduced levels of LPS-stimulated NF-kappaB regulated proinflammatory IL-1beta and macrophage inflammatory protein-1alpha expression and increased antiinflammatory IL-10 expression in lung alveolar macrophages of Fra-1-null mice in vivo. Thus, our studies indicate that NF-kappaB 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. |
