Clash of the Cytokine Titans: counter-regulation of interleukin-1 and type I interferon-mediated inflammatory responses

Abstract

Over the past decades the notion of 'inflammation' has been extended beyond the original hallmarks of rubor (redness), calor (heat), tumor (swelling) and dolor (pain) described by Celsus. We have gained a more detailed understanding of the cellular players and molecular mediators of inflammation which is now being applied and extended to areas of biomedical research such as cancer, obesity, heart disease, metabolism, auto-inflammatory disorders, autoimmunity and infectious diseases. Innate cytokines are often central components of inflammatory responses. Here, we discuss how the type I interferon and interleukin-1 cytokine pathways represent distinct and specialized categories of inflammatory responses and how these key mediators of inflammation counter-regulate each other.

Figure 1

Cross-regulation between interleukin-1 (IL-1) and type-1 interferon (IFN) inflammatory pathways as exemplified during Mtb infection. Mtb infection triggers both cytosolic nucleotidyltransferase GAMP synthase-STING-TBK1-interferon regulatory transcription factor 3-interferon-β (cGAS-STING-TBK1-IRF3-IFN-β) axis and AIM2/NLRP3-IL-1β pathway in myelophagocytic cells. These two pathways exert opposite biological outcomes for host defense against Mtb: IL-1 is recognized as beneficial with anti-bacterial effects while type I IFNs are considered largely detrimental with replication promoting properties. IL-1α and IL-1β limit type I IFN production through direct transcriptional downregulation and PTGS2-mediated PGE2 production, which in turn inhibits type I IFN. Type I IFNs attenuate IL-1α/β signaling through induction of IL-10, IL-1R2, IL-1RA and CH25H.