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 immune and inflammatory responses [1], [2].

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) [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 protein Toll interacting protein (TOLLIP) forms a complex with IRAK1 in resting cells and inhibits IL-1-induced signaling by blocking IRAK1 phosphorylation [5], [6], [7]. 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) [1], [7].

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)) [8], [9].

TAK1 also phosphorylates and activates Mitogen-activated protein kinase kinase kinase 14 (NIK) that phosphorylates IKK-alpha and stimulates its activity [10].

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 (Tissue factor) and proinflammatory cytokines, such as Tumor necrosis factor (TNF-alpha), Interleukin 6 (IL-6) and Interleukin 8 (IL-8) [7], [8], [9], [11], [12], [13], [14], [15], [16], [17].

Another signaling pathway, TRAF6/ ECSIT homolog (SITPEC)/ Mitogen-activated protein kinase kinase kinase 1 (MEKK1), activates both NF-kB p50/p65 and AP-1 [18].

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) [7], [19], [20], [21], [22].

p38alpha also phosphorylates Signal transducer and activator of transcription 1 (STAT1) which up-regulates IRF1 expression. STAT1 and IRF1 are involved in iNOS expression [13], [19].

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. [19], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36].

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