Immune response IL-1 signaling pathway
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 immuneand inflammatory responses [1], [2].
There are two forms of IL-1 encoded by distinct genes, IL-1 alpha and IL-1beta. IL-1 induces cellular response through its receptor composed of two subunits,Interleukin 1 receptor type I ( IL-1RI ) and Interleukin 1 receptor accessoryprotein ( IL1RAP ) [3], [4].
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 proteinToll interacting protein ( TOLLIP ) forms a complex with IRAK1 in restingcells and inhibits IL-1-induced signaling by blocking IRAK1 phosphorylation [5], [6], [7]. IRAK4 phosphorylates and activatesIRAK1. The latter subsequently associates with TNF receptor-associated factor 6 (TRAF6 ) causing oligomerization and activation of TRAF6 that stimulates twodistinct signaling pathways leading to the activation of transcription factors Nuclearfactor kappa-B ( NF-kB p50/p65 ) and Activator protein 1 ( AP-1 ) [7], [1].
TRAF6 is a ubiquitin ligase (E3) that functions with the ubiquitin conjugating(E2) complex consisting of Ubiquitin-conjugating enzyme E2 variant 1 ( UEV1A ) andUbiquitin-conjugating enzyme E2N ( UBC13 ) to catalyze the synthesis ofLys63-linked polyubiquitin chains on target proteins including TRAF6 itself.Ubiquitinated TRAF6 then forms a complex with Mitogen-activated protein kinasekinase kinase 7 interacting proteins 1 and 2 ( TAB1 and TAB2 ) andMitogen-activated protein kinase kinase kinase 7 ( TAK1 ). TAK1phosphorylates the Inhibitor of kappa light polypeptide gene enhancer in B-cells kinasebeta ( 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 polypeptidegene 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) ) [8], [9].
TAK1 also phosphorylates and activates Mitogen-activated protein kinase kinasekinase 14 ( NIK ) that phosphorylates IKK-alpha and stimulates its activity[10].
IKK (cat) then phosphorylates the Inhibitor of NF-kB ( I-kB ), leadingto its ubiquitylation and subsequent degradation. This allows NF-kB p50/p65 totranslocate 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 )[11], [7], [12], [13], [14],[8], [15], [16], [17], [9].
Another signaling pathway, TRAF6/ ECSIT homolog ( SITPEC )/Mitogen-activated protein kinase kinase kinase 1 ( MEKK1 ), activates bothNF-kB p50/p65 and AP-1 [18].
TAK1 and MEKK1 are responsible for the phosphorylation and activation ofmitogen-activated protein kinase kinases 3, 4 and 6 ( MEK3, MEK4 andMEK6 ). The three MEKs phosphorylate and activate Mitogen-activated proteinkinases 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-Junhomodimer ( c-Jun/c-Jun ) [19], [20], [7],[21], [22].
p38alpha also phosphorylates Signal transducer and activator of transcription 1( STAT1 ) which up-regulates IRF1 expression. STAT1 and IRF1are involved in iNOS expression [19], [13].
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 andIL-8. [23], [24], [25], [26], [19], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36].
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