TAK1 knockdown enhances lipopolysaccharide-induced secretion of proinflammatory cytokines in myeloid cells via unleashing MEKK3 activity.

Abstract TGF-β activating protein kinase 1 (TAK1) belongs to the MAP kinase kinase kinase (MAP3K) family. TAK1 is involved in many signaling pathways, especially the innate and adaptive immune responses. TAK1 mediates nuclear factor κB (NF-κB) and MAPK signaling pathway in response to interleukin-1, tumor necrosis factor-α (TNFα), and toll-like receptor agonists, such as lipopolysaccharide (LPS). The regulatory roles of TAK1 in LPS-induced proinflammatory cytokines production are dependent on the cell types. In this study, we examined the effects of TAK1 on the LPS induced production of proinflammatory cytokines in myeloid cells. Knockdown of TAK1 enhanced the secretion of interleukin 1-beta (IL-1β) and TNFα induced by LPS. In addition, LPS-activated TAK1 negatively regulates mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3). Moreover, TAK1 inhibited MEKK3 activation, which, in turn, activated NF-κB. These results indicate that TAK1 negatively regulates LPS-induced cytokine secretion in myeloid cells by inhibiting MEKK3 activities.