IL-1 Pathway
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IL-1 Pathway

IL-1 (Interleukin-1) is a proinflammatory cytokine that stimulates a broad spectrum of immune and inflammatory responses. IL-1 is produced by activated macrophages, endothelia cells, B-Cells, and fibroblast cells. It induces inflammatory responses, edema, promotes the production of Prostaglandins, IL-2, and the growth of leukocytes (Ref.1). There are two forms of IL-1 encoded by distinct genes, IL-1Alpha and IL-1Beta. IL-1Beta is produced as a 269 amino acid precursor that is cleaved by ICE (IL-1Beta Converting Enzyme) to the active IL-1 Beta form that is secreted. IL-1 induces cellular response through two subunits of its receptor, IL-1R1 (IL-1 Receptor1) and IL-1RAcP (IL-1 Receptor Accessory Protein). When it binds to its cell-surface receptor, IL-1 initiates a signaling cascade that leads to activation of the transcription factors like NF-KappaB (Nuclear Factor-KappaB), Activating Protein-1, and ATF (Activating Transcription Factor), thus stimulating the expression of various genes in different target cells (Ref.2).

After IL-1 is bound, a complex is formed between the type 1 receptor and the receptor accessory protein. The cytosolic proteins MyD88 (Myeloid Differentiation primary response gene-88) and TollIP (Toll-Interacting Protein) are recruited to this complex, where they function as adaptors, recruiting IRAK(IL-1 Receptor-Associated Kinase) in turn. IRAK1, a serine-threonine kinase, activates and recruits TRAF6 (TNF Receptor-Associated Factors-6) to the IL-1 receptor complex. Eventually, phosphorylated IRAK is ubiquitinated and degraded. TRAF6 activates two pathways, one leading to NF-KappaB activation and another leading to c-Jun activation. The TRAF associated protein ECSIT leads to c-Jun activation through the MAPK (Mitogen Activated Protein Kinase)/JNK(Jun N-terminal Kinases) signaling system (Ref.3). TRAF6 also signals through the TAB1 (TAK1 Binding Protein-1)/TAK1 (TGF-Beta-Activating Kinase-1) kinases to trigger the degradation of I-KappaB, and activation of NF-KappaB. TAK1 and two interacting proteins, TAB1 and TAB2 play important role in IL-1 signaling. TAB2 translocates to the cytosol upon stimulation with IL-1, where it functions as an adaptor, linking TRAF6 to TAK1 and TAB1. Activated TAK1 activates NIK (NF-KappaB-Inducing Kinase) directly, leading to the activation of IKK (I-KappaB Kinases) and thus to the phosphorylation and degradation of I-KappaB. NF-KappaB is then translocated to the nucleus to activate transcription (Ref.4).

Binding of IL-1 to its cell surface receptor also activates a pertussis toxin-sensitive G-proteins, which in turn stimulates AC (adenylate cyclase) activity and thus increases the intracellular level of cAMP (Cyclic Adenosine Monophosphate). cAMP activates cAMP-dependent protein kinase(s) which induce(s) the activation of NF-KappaB, a DNA binding protein that plays an important role in the transcriptional regulation of the HIV-LTR and the Kappa Ig gene in pre-B-Cells (Ref.5). IL-1 is a pivotal pro-inflammatory cytokine centrally involved in local and systemic responses in the immune system leading to typical effects of inflammation. Dysregulated, prolonged synthesis and release of IL-1 in chronic inflammatory situations contributes to many diseases, e.g. rheumatoid arthritis. IL-1 also augments Corticosteroid release, induces fever and shivering.