Cytokines play a crucial role overseeing the correct functioning of the immune system. Interleukin-6 (IL-6) is a critical immune-modulatory cytokine that helps to initiate and sustain the inflammatory response. The IL-6–Janus kinase (JAK)–STAT3 signalling is important for cancers resulting from the activation of the intrinsic inflammatory pathway. Yet, despite its relevancy for human health, we have a poor understanding of how IL-6 elicits its pleiotropic activities.
Publishing in Cell Reports today, the Moraga lab has uncovered a new role of the transcriptional regulator cyclin dependent kinase-8 (CDK8) in regulating IL-6 responses. CDK8 and STAT3 interact in the nucleus upon IL-6 stimulation, leading to STAT3 Serine phosphorylation. Inhibition of CDK8 results in a more sustained STAT3 Tyrosine phosphorylation and nuclear retention. Overall, the research provides new experimental evidence that CDK8 regulates STAT3 chromatin binding dwell-time and transcriptional activities, which could have important implications in STAT3 mediated diseases and inflammation.
Dr Ignacio Moraga said "The role of serine phosphorylation of STAT3 in cytokine mediated activities has been somewhat controversial. Our study identifies serine phosphorylation of STAT3 by CDK8 as key to regulating STAT3 nuclear dynamics. This opens up new avenues to manipulate IL-6 and STAT3 mediates responses, and represents a new potential strategy to harness the therapeutic potential of cytokines.”
This study was a collaboration with colleagues at Purdue University (USA) and INSERM, France and was supported by Wellcome, the European Research Council and the National Heart, Lung and Blood Institute.