IL1 signaling (Homo sapiens)

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The IL-1 family of cytokines currently consists of 11 members which are encoded by distinct genes and includes IL-1α, IL-1β, and the IL-1 Receptor antagonist (IL-1RA). The major role of IL-1 type cytokines is to control pro-inflammatory reactions in response to tissue injury - either due to pathogen-associated molecular patterns (PAMPs) or Danger associated molecular patterns (DAMPs). Interleukin-1 (IL-1), which includes IL-1α and IL-1β, plays a crucial role in many auto inflammatory diseases. IL- 1α and IL-1β are produced predominantly by macrophages and monocytes, and to a lesser extent by other cell types such as epithelial cells endothelial cells and fibroblasts. IL-1 alpha, is a membrane anchored protein which signals through autocrine or juxtracrine mechanisms where as the soluble IL-1β acts in a paracrine or systemic manner. Significant progress has been achieved in the study of the signaling events mediated by IL-1 and the processes they control. Involvement of IL-1α or IL-1β in host responses to infections caused by intracellular microorganisms such as Mycobacterium tuberculosis as well as in autoinflammatory diseases makes its signaling components important candidates for drug targetting for these diseases. The two forms of IL-1 (IL-1α and IL-1β) bind to the same cellular receptor, the Type I IL- 1 receptor (IL-1RI) to induce signaling. Upon receptor engagement, IL-1R1 forms a heterodimer with IL-1 receptor accessory protein (IL-1RAcP), which functions as a co receptor. IL-1RAcP cannot bind directly to IL-1 but is essential for IL-1-mediated signaling. Binding of IL-1 to this receptor complex leads to the activation of the transcription factor NF-κB through different signaling mechanisms. Two IL-1 receptor-associated kinases, IRAK-1 and IRAK-2 have been implicated in the activation of NF-κB. IRAK 1 and 2 functions as adapter proteins and protein kinases to transmit downstream signals. It recruits TRAF6 to the IL-1 receptor complex via an interaction with IL-1RAcP. Oligomerization of TRAF6 and subsequent formation of TAK1 and MEKK3 signaling complexes relays the signal via NF-κB-inducing kinase (NIK) to two I-kappaB kinases (IKK-1 and -2), leading to NF-kappaB activation. Activation of other mitogen activated protein kinases, including JNKs and p38 MAPK through various MAP2Ks also play important roles in mediating IL-1 responses by activating transcription through the AP-1 transcription factor. The above mentioned signaling events co-operatively induce the expression of IL-1 target genes such as CCL2, IL-8 and IL-6. The interactions and intersections between canonical and non-canonical Interleukin-1 signaling systems are depicted in the pathway map. Regulation of IL-1 signaling can be brought about by various mechanisms. The IL-1 family member IL-1RA can bind to the IL1-R1 receptor with similar affinity as IL-1α and β, but is incapable of activating the signaling response. The type II IL-1 receptor can bind to IL-1 alpha and beta but lacks signaling capacity. The naturally occurring 'shed' domains of the extracellular IL-1 receptor chains (IL-1RI, IL-1RII and IL- 1RAcP) also act as inhibitors of IL-1 signaling. In the cell, IL-1R binds to toll- interacting protein (TOLLIP), which results in the inhibition of IRAK1 and by promoting efficient degradation of IL-1R by targeting the internalized receptor to endosomes. Other mechanisms such as p38MAPK mediated phosphorylation of TAB1 which results in the inactivation of TAK1, and expression of genes including MAPK phosphatase 1 (MKP-1) and Inhibitor of kappa B alpha (NFKBIA) that inhibit IL-1 signaling components also serve as negative regulators of IL-1 signaling.