IL-1 signaling pathway

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. Please access this pathway at [http://www.netpath.org/netslim/IL_1_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. Genome Biology. 11:R3.

白介素-1（IL-1）家族目前包含11个成员，这些成员由不同的基因编码，包括IL-1α、IL-1β以及白介素-1受体拮抗剂（IL-1RA）。IL-1型细胞因子在调控组织损伤后的促炎反应中扮演主要角色，这种损伤可能是由于病原体相关分子模式（PAMPs）或危险相关分子模式（DAMPs）所致。白介素-1（包括IL-1α和IL-1β）在众多自身炎症性疾病中发挥着至关重要的作用。IL-1α和IL-1β主要由巨噬细胞和单核细胞产生，在一定程度上也由其他细胞类型如上皮细胞、内皮细胞和成纤维细胞产生。IL-1α是一种膜锚定蛋白，通过自分泌或旁分泌机制进行信号传导，而可溶性IL-1β则以局部或全身方式发挥作用。关于IL-1介导的信号传导事件及其调控过程的研究取得了显著进展。IL-1α或IL-1β在宿主对结核分枝杆菌等胞内微生物引起的感染以及自身炎症性疾病中的反应中发挥作用，因此，其信号传导成分是这些疾病药物靶向的重要候选者。两种形式的IL-1（IL-1α和IL-1β）与同一种细胞受体——I型IL-1受体（IL-1RI）结合，以诱导信号传导。受体结合后，IL-1R1与IL-1受体辅助蛋白（IL-1RAcP）形成异源二聚体，后者作为共受体发挥作用。IL-1RAcP不能直接与IL-1结合，但对于IL-1介导的信号传导是必不可少的。IL-1与该受体复合物的结合通过不同的信号传导机制激活转录因子NF-κB。两种IL-1受体相关激酶，IRAK-1和IRAK-2，在NF-κB的激活中起作用。IRAK 1和2作为适配蛋白和蛋白激酶传递下游信号，并通过与IL-1RAcP相互作用将TRAF6募集到IL-1受体复合物。TRAF6的寡聚化及其随后的TAK1和MEKK3信号复合物的形成通过NF-κB诱导激酶（NIK）将信号传递到两个I-κB激酶（IKK-1和-2），导致NF-kappaB的激活。通过不同的MAP2Ks激活其他有丝分裂原激活蛋白激酶，包括JNKs和p38 MAPK，通过激活AP-1转录因子来介导IL-1反应，也发挥着重要作用。上述信号传导事件协同诱导IL-1靶基因如CCL2、IL-8和IL-6的表达。经典和非经典白介素-1信号系统之间的相互作用和交叉在通路图中得以展示。IL-1信号传导的调控可以通过多种机制实现。IL-1家族成员IL-1RA可以与IL1-R1受体以与IL-1α和β相似的亲和力结合，但不能激活信号传导反应。II型IL-1受体可以与IL-1α和β结合，但缺乏信号传导能力。细胞外IL-1受体链（IL-1RI、IL-1RII和IL-1RAcP）的天然“脱落”结构域也作为IL-1信号传导的抑制剂。在细胞中，IL-1R与toll相互作用蛋白（TOLLIP）结合，导致IRAK1的抑制并促进通过将内吞受体靶向到内体来有效地降解IL-1R。其他机制，如p38MAPK介导的TAB1磷酸化导致TAK1失活，以及表达包括MAPK磷酸酶1（MKP-1）和κB抑制因子α（NFKBIA）等基因抑制IL-1信号传导成分，也作为IL-1信号传导的负调控因子。请访问[http://www.netpath.org/netslim/IL_1_pathway.html NetSlim]数据库获取此通路。如使用此通路，请引用以下论文：Kandasamy, K. 等人 (2010). NetPath: A public resource of curated signal transduction pathways. Genome Biology. 11:R3.