c-Jun is required for nuclear factor-κB–dependent, LPS-stimulated Fos-related antigen-1 transcription in alveolar macrophages

RK Mishra, HR Potteti, CR Tamatam… - American Journal of …, 2016 - atsjournals.org
RK Mishra, HR Potteti, CR Tamatam, I Elangovan, SP Reddy
American Journal of Respiratory Cell and Molecular Biology, 2016atsjournals.org
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 …
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.
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