LYATK1 potently inhibits LPS-mediated pro-inflammatory response

Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-beta-activated kinasel (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAKI inhibited LPS-induced mRNA expression and production of several pro -inflammatory cytokines [interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha(TNF alpha) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro -inflammatory cytokine production was again attenuated with LYTAKI co-treatment. Molecularly, LYTAKI dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NF kappa B) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAKI inhibited LPS-induced activation of TAK1-NF kappa B-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAKI inhibits LPS-induced production of several pro -inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. (C) 2015 Elsevier Inc. All rights reserved.