The IL-1 family cytokines, including IL-1, IL-33 and IL-36, control T helper cell differentiation into various T helper cell lineages such as Th1, Th2 and Th17 cells. These cytokines are important messenger molecules for mounting immune responses to infection, but also can lead to chronic inflammatory diseases. For instance, IL-33 drives T cell lineage commitment to Th2 cells and is critically important in the progression and exacerbation of asthma; IL-36 drives T cells to become Th1 cells and is a key pathogenic component of psoriasis. All of these cytokines function in similar ways: they bind their cognate receptors and recruit the common IL-1 receptor accessory protein (IL-1RAcP), bringing together cytoplasmic TIR domains from each that initiates signal transduction. Several mechanisms exist to regulate the activation of these cytokine signaling pathways, including antagonist cytokines that compete for binding to cognate receptors but inhibit IL-1RAcP recruitment, as well as decoy receptors that do not include TIR domains and, thus, cannot signal. We are determining the molecular determinants of agonist and antagonist signaling through ST2 (the IL-33 receptor) and the IL-36 receptor and utilizing this knowledge to engineer super-antagonists and improved decoy receptors of IL-33 and IL-36 signaling. We are also adopting a strategy of designing decoy peptide inhibitors that is highly effective in blocking Toll-like receptor signaling (TLRs also have cytoplasmic TIR domains) to IL-1 family cytokine signaling.
Selected recent publications:
Sebastian Günther, Daniel Deredge, Amanda L. Bowers, Alessandra Luchini,Daniel A. Bonsor, Robert Beadenkopf, Lance Liotta, Patrick L. Wintrode and Eric J. Sundberg(2017). IL-1 family cytokines use distinct molecular mechanisms to signal through their shared co-receptor. Immunity, 47(3), 510-523.e4.
Sebastian Günther and Eric J. Sundberg* (2014). Molecular determinants of agonist and antagonist signaling through the IL-36 receptor. Journal of Immunology, 193(2), 921-930