UEV1A, COX-2, UBC13, IL1RAP, MEK4, NF-kB p50/p65, NIK, AP-1, p38alpha , TAB1, IKK-alpha, IRAK4, TRAF6, STAT1, IL-1 alpha, MEK6, TAK1, MEKK1, Endothelin-1, iNOS, IL-6, JNK(MAPK8-10), TNF-alpha, MyD88, IL-1RI, IL-8, IKK-gamma, IKK (cat), F3, IL-1 beta, PAI1, c-Jun/c-Jun, IKK-beta, Ceruloplasmin, MEK3, TOLLIP, IRF1, c-Jun, Ubiquitin, IRAK1, TAB2, SITPEC, I-kB, Heme oxygenase 1
IL-1 signaling pathway
Interleukin-1 (IL-1) is a proinflammatory cytokine produced by activated macrophages, endothelial cells, B cells and fibroblasts. IL-1 stimulates a broad spectrum of immune and inflammatory responses , .
There are two forms of IL-1 encoded by distinct genes, IL-1 alpha and IL-1 beta. IL-1 induces cellular response through its receptor composed of two subunits, Interleukin 1 receptor type I ( IL-1RI ) and Interleukin 1 receptor accessory protein ( IL1RAP ) , .
Activated by binding of either of its ligands IL-1 alpha and IL-1 beta, IL-1RI binds to the adaptor protein Myeloid differentiation primary response gene 88 ( MyD88 ) that activates Interleukin-1 receptor-associated kinase 4 ( IRAK4 ) and Interleukin-1 receptor-associated kinase 1 ( IRAK1 ). The adaptor protein Toll interacting protein ( TOLLIP ) forms a complex with IRAK1 in resting cells and inhibits IL-1-induced signaling by blocking IRAK1 phosphorylation , , . IRAK4 phosphorylates and activates IRAK1. The latter subsequently associates with TNF receptor-associated factor 6 ( TRAF6 ) causing oligomerization and activation of TRAF6 that stimulates two distinct signaling pathways leading to the activation of transcription factors Nuclear factor kappa-B ( NF-kB p50/p65 ) and Activator protein 1 ( AP-1 ) , .
TRAF6 is a ubiquitin ligase (E3) that functions with the ubiquitin conjugating (E2) complex consisting of Ubiquitin-conjugating enzyme E2 variant 1 ( UEV1A ) and Ubiquitin-conjugating enzyme E2N ( UBC13 ) to catalyze the synthesis of Lys63-linked polyubiquitin chains on target proteins including TRAF6 itself. Ubiquitinated TRAF6 then forms a complex with Mitogen-activated protein kinase kinase kinase 7 interacting proteins 1 and 2 ( TAB1 and TAB2 ) and Mitogen-activated protein kinase kinase kinase 7 ( TAK1 ). TAK1 phosphorylates the Inhibitor of kappa light polypeptide gene enhancer in B-cells kinase beta ( IKK-beta ), a subunit of the Inhibitor of kB kinase complex (IKK complex). IKK complex is composed of one regulatory subunit, Inhibitor of kappa light polypeptide gene enhancer in B-cells kinase gamma ( IKK-gamma ), and two catalytic subunits, Conserved helix-loop-helix ubiquitous kinase ( IKK-alpha ) and IKK-beta, forming the IKK complex catalytic core ( IKK (cat) ) , .
TAK1 also phosphorylates and activates Mitogen-activated protein kinase kinase kinase 14 ( NIK ) that phosphorylates IKK-alpha and stimulates its activity .
IKK (cat) then phosphorylates the Inhibitor of NF-kB ( I-kB ), leading to its ubiquitylation and subsequent degradation. This allows NF-kB p50/p65 to translocate into the nucleus and induce the expression of Interferon regulatory factor 1 ( IRF1 ), Heme oxygenase 1, Prostaglandin-endoperoxide synthase 2 ( COX-2 ), Nitric oxide synthase 2A ( iNOS ), Coagulation factor III ( F3 ) and proinflammatory cytokines, such as Tumor necrosis factor ( TNF-alpha ), Interleukin 6 ( IL-6 ) and Interleukin 8 ( IL-8 ) , , , , , , , , , .
Another signaling pathway, TRAF6/ ECSIT homolog ( SITPEC )/ Mitogen-activated protein kinase kinase kinase 1 ( MEKK1 ), activates both NF-kB p50/p65 and AP-1 .
TAK1 and MEKK1 are responsible for the phosphorylation and activation of mitogen-activated protein kinase kinases 3, 4 and 6 ( MEK3, MEK4 and MEK6 ). The three MEKs phosphorylate and activate Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ) and Mitogen-activated protein kinase 14 ( p38alpha ) leading to phosphorylation of the AP-1 subunit, Jun oncogene ( c-Jun ) and activation of AP-1 transcription factors, including c-Jun homodimer ( c-Jun/c-Jun ) , , , , .
c-Jun-containing AP-1 complexes induce the expression of Heme oxygenase 1, F3, Endothelin-1, Plasminogen activator inhibitor-1 ( PAI1 ), Ceruloplasmin and multiple cytokines, including TNF-alpha, IL-6 and IL-8. , , , , , , , , , , , , , , .