Relationship among Toll-like receptors, β2 adrenergic receptor, and mitogen-activated protein kinases in regulating <i>Il1b</i> transcription

The β2-adrenergic receptor (β2AR) signaling suppresses the activation of key inflammatory genes in Toll-like receptor (TLR) stimulated macrophages, but Il1b transcription is activated by β2AR signaling. The β2ARs potently activate protein kinase A and CREB, but other signaling pathways can also be activated, including mitogen-activated protein kinase (MAPK) pathways. Prior studies have shown that β2AR activation of Il1b transcription is dependent on MAPK signaling, raising the question of how this regulatory pathway intersects with TLR signaling, which also activates many genes in a MAPK-dependent manner. Here, we strengthened prior evidence that β2AR signaling activates early Il1b transcription and interleukin-1β secretion. We then examined the relationship among β2AR, TLR, and MAPK signaling at a genome-wide scale in macrophages treated with β2AR agonists alone or in combination with LPS. By RNA-seq analysis, we observed that a select subset of β2AR-activated genes, including Il1b, were among a set of genes that also depend on MAPKs for their induction by TLR4. However, as several LPS-induced, MAPK-dependent genes were repressed by β2AR signaling, the regulation of MAPK-dependent genes by β2AR signaling is not simply due to a global effect of enhanced MAPK signaling. ATAC-seq analysis provided evidence that AP-1 family members are involved in MAPK-dependent transcriptional induction by β2AR, with β2AR signaling acting primarily on genomic regions that exhibit constitutive chromatin accessibility or TLR4-induced accessibility. Together, our results highlight the complex relationship among β2AR, TLR, and MAPK signaling, with β2AR-induced MAPK signaling contributing to the activation of a select subset of MAPK-dependent TLR target genes.