A Resorcylic Acid Lactone, 5Z-7-Oxozeaenol, Prevents Inflammation by Inhibiting the Catalytic Activity of TAK1 MAPK Kinase Kinase

Abstract

TAK1, a member of the mitogen-activated kinase kinase kinase (MAPKKK) family, participates in proinflammatory cellular signaling pathways by activating JNK/p38 MAPKs and NF-B. To identify drugs that prevent inflammation, we screened inhibitors of TAK1 catalytic activity. We identified a natural resorcylic lactone of fungal origin, 5Z-7-oxozeaenol, as a highly potent inhibitor of TAK1. This compound did not effectively inhibit the catalytic activities of the MEKK1 or ASK1 MAPKKKs, suggesting that 5Z-7-oxozeaenol is a selective inhibitor of TAK1. In cell culture, 5Z-7-oxozeaenol blocked interleukin-1-induced activation of TAK1, JNK/ p38 MAPK, IB kinases, and NF-B, resulting in inhibition of cyclooxgenase-2 production. Furthermore, in vivo 5Z-7-oxozeaenol was able to inhibit picryl chlorideinduced ear swelling. Thus, 5Z-7-oxozeaenol blocks proinflammatory signaling by selectively inhibiting TAK1 MAPKKK.TAK1 is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) 1 family that phosphorylates and activates MKK3, MKK4, MKK6, and MKK7 MAPKKs, which in turn activate the c-Jun N-terminal kinase (JNK) and p38 MAPKs (1-3). We have recently demonstrated that TAK1 also activates IB kinases (IKKs), ultimately leading to activation of the transcription factor NF-B (4). TAK1 participates in proinflammatory cellular signaling pathways such as the interleukin-1 (IL-1) pathway by activating both JNK/p38 MAPKs and IKKs. Exposure of cells to IL-1 induces the interaction between endogenous TAK1 and TRAF6 (tumor necrosis factor (TNF) receptor-associated factor 6), a molecule essential for IL-1 activation of both JNK/p38 and NF-B. This interaction in turn leads to TAK1 activation. We have previously identified two TAK1-binding proteins, TAB1 and TAB2 (5, 6). When ectopically co-expressed, TAB1 augments the kinase activity of TAK1, indicating that TAB1 functions as an activator of TAK1 (5, 7). TAB2 functions as an adaptor linking TAK1 to TRAF6 by directly binding to both, thereby mediating TAK1 activation in the IL-1 signaling pathway (6,8).Several lines of evidence suggest that TAK1 is a key molecule in proinflammatory signaling pathways. Various proinflammatory cytokines and endotoxins activate the kinase activity of endogenous TAK1 (4, 9, 10). Overexpression of kinase-dead TAK1 inhibits IL-1-and TNF-induced activation of both JNK/p38 and NF-B (4, 10). The Drosophila homolog of TAK1 was recently identified as an essential molecule for host defense signaling in Drosophila (11). Furthermore, the TAK1 gene-silencing study using the small interfering RNA method defined that TAK1 is essential for both IL-1-and TNF-induced NF-B activation in mammalian cells (12). Therefore, it can be expected that inhibition of TAK1 activity may be effective in preventing inflammation and tissue destruction promoted by proinflammatory cytokines.In this study, we screened for compounds that can inhibit TAK1 kinase activity. This strategy resulted in the isolation of one natural compound 5Z-7-oxozeaenol, a resorcylic lactone of fungal ori...

Kinase Inhibition by Deoxy Analogues of the Resorcylic Lactone L-783277

“…Further modification of 1 by a change in double bond geometry from Z to E, to produce 2, or the removal of the OH group on C4 0 , to give 3, lead to a significant loss in potency, although both compounds retain clearly submicromolar activity against VEGFR2 and PDGFRR (V561D). The data for E analogue 2 provide broad confirmation for the substantially reduced activity of C7 0 -C8 0 E-configured RL-based kinase inhibitors, which had been reported previously for the C7 0 -C8 0 E isomers of L-783277 and LL-Z1640-2 against MEK2 29 and TAK1, 31 respectively, and also for E-LL-Z1640-2 in a cellular reporter assay for TNFR signaling. 18 There appears to be a trend for 3 to be more potent than 2, but additional data are required to consolidate this conclusion.…”

TAK1 control of cell death

“…Thus, inhibition of TAK1 is one of the most promising approaches to therapeutic cell killing, as proposed also in recent cancer studies. 102,105 This further emphasizes the importance of studies elucidating the regulatory mechanisms of TAK1 in the cell death network.…”

“…It has thus far been clear that the necroptosis-mediated inhibition of apoptosis possesses unique and complex features. Only manipulation of TAK1 induces predictable outcomes, in which both deletion of Tak1 gene and inhibition of TAK1 by a selective inhibitor, 5Z-7-oxozeaenol, 102 activates apoptotic cell death. 103,104 In contrast, it is very puzzling that inhibition and gene deletion of RIPK1 and RIPK3 result in different phenotypes.…”

A Cytosolic ATM/NEMO/RIP1 Complex Recruits TAK1 To Mediate the NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK)/MAPK-Activated Protein 2 Responses to DNA Damage

“…To examine a requirement for the kinase activity of TAK1, we pretreated cells with vehicle or with 5Z7, a potent and highly selective inhibitor of TAK1 (Bioaustralis) (18,23,26). The cells were left untreated or exposed to the proinflammatory cytokine TNF-␣ for 10 min or to doxorubicin for the time periods indicated in Fig.…”