Molecular mechanisms underlying the regulation of interleukin-10 production in macrophages

Interleukin (IL)-10 is an immunosuppressive cytokine that plays a crucial role in preventing inflammatory and autoimmune pathology. The dysregulation of IL-10 during infection can lead to either an over-exuberant response damaging the host, or conversely ineffective pathogen clearance. Macrophages are important players in inflammatory responses and produce IL-10 in response to Toll-like receptor (TLR) ligation along with protective pro-inflammatory cytokines. The collective regulation of these cytokines is central to the generation of an effective but balanced immune response. We observed that type I IFN is one factor that leads to differential production of IL-10 and pro-inflammatory cytokines in TLR4 stimulated C57BL/6 and BALB/c macrophages. The effects of type I IFN on pro-inflammatory cytokine production were IL-10 dependent and independent. Hence, we further investigated how type I IFN regulates IL-10 production and showed that type I IFN acts as a transcriptional regulator of Il10 mRNA via activation of ERK1/2, and additionally stabilises Il10 mRNA transcripts in TLR4 stimulated macrophages. Using an assay for transposase-accessible chromatin with high throughput sequencing we further unravelled how type I IFN regulates Il10 transcription. We were able to demonstrate that type I IFN increases chromatin accessibility and augments the recruitment of the transcription factors ATF3 and JUNB to the Il10 locus in macrophages upon LPS stimulation. These findings highlight key pathways responsible for the type I IFN-dependent regulation of IL-10, and may provide valuable information for the development of immunomodulatory treatments of inflammatory diseases