The pro-inflammatory cytokine IL-1 is a critical regulator of the innate immune response and the interleukin-1 (IL-1)-mediated signal transduction is a paradigm of immune signalling. Our goal is to understand the molecular details of the IL-1-induced signalling pathways. These pathways are activated by many other receptors, e.g. the Toll-like receptor (TLRs), and are important for the inflammatory response to combat pathogens, but are also involved in the development of autoimmune diseases like arthritis and psoriasis. Thus, a better understanding of proinflammatory signal transduction pathways may lead to the identification of novel drug targets and more effective therapies.
In the current model of IL-1R/TLR Signalling IRAK1 and IRAK4 are recruited to the IL-1R/TLR via their interaction with MyD88 (1). IRAK4 is activated and phosphorylates IRAK1. Autophosphorylation of IRAK1 leads then to the recruitment of TRAF6 and to the dissociation of IRAK1 from MyD88 (2). TRAF6 is thought to ubiquitinate IRAK1 with K63-linked polyubiquitin chains, whereas the LUBAC complex consisting of HOIP, HOIL-1 and SHARPIN catalyzes the formation of M1-linked polyubiquitin chains. These events induce the recruitment of the TAK1 and IKK kinase complexes. Both kinase complexes are recruited via polyubiquitin-binding subunits: TAB2 (TAK1-binding protein 2) binds K63-linked chains and NEMO (IKKgamma) M1-linked chains, respectively. TAK1 is activated most likely by autophosphorylation and phosphorylates IKKalpha/beta. The IKK complex activates Tpl2/Cot via the phosphorylation and subsequent degradation of p105 (NFkappaB1) and NF-kappaB via phosphorylation and degradation of IkappaB (3). TAK1 is thought to be released to the cytosol to activate MKKs (4).
Recently we discovered an important role for the small GTPase Rac1 in IL-1 signalling. Interestingly, the IL-1-dependent activation of Rac1 depends on the internalization of the IL-1 receptor. Thus, we propose a two-tiered model of IL-1 signalling. The IL-1-induced gene expression is regulated by events that are initiated from the plasma membrane as well as from signalling endosomes after receptor internalization. Upstream activators and downstream effectors of Rac1 remain to be identified.
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