CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci

Summary Cytokines are highly pleiotropic ligands that regulate the immune response. Here, using interleukin-6 (IL-6) as a model system, we perform detailed phosphoproteomic and transcriptomic studies in human CD4+ T helper 1 (Th-1) cells to address the molecular bases defining cytokine functional pleiotropy. We identify CDK8 as a negative regulator of STAT3 transcriptional activities, which interacts with STAT3 upon IL-6 stimulation. Inhibition of CDK8 activity, using specific small molecule inhibitors, reduces the IL-6-induced phosphoproteome by 23% in Th-1 cells, including STAT3 S727 phosphorylation. STAT3 binding to target DNA sites in the genome is increased upon CDK8 inhibition, which results in a concomitant increase in STAT3-mediated transcriptional activity. Importantly, inhibition of CDK8 activity under Th-17 polarizing conditions results in an enhancement of Th-17 differentiation. Our results support a model where CDK8 regulates STAT3 transcriptional processivity by modulation of its gene loci resident time, critically contributing to diversification of IL-6 responses.
Graphical Abstract
Highlights • CDK8 regulates IL-6-mediated STAT3 S727 phosphorylation in primary human T cells • CDK8 controls STAT3 activity by limiting its resident time at gene loci • CDK8 inhibition increases IL-6-mediated Th17 differentiation
How IL-6 elicits its immune pleiotropic activities is not fully understood. Martinez-Fabregas et al. show that CDK8 represses IL-6-mediated transcription by limiting STAT3 resident time at the gene loci. By regulating CDK8 expression levels, immune cells can adapt their responses to STAT3-activating cytokines.