Activation of TOPK by lipopolysaccharide promotes induction of inducible nitric oxide synthase through NF-kappa B activity in leukemia cells

Abstract

T-LAK cell-originated protein kinase (TOPK) is known to be involved in tumorigenesis or cancer progression. However, the role of TOPK in inflammatory response remains elusive. Here we show that TOPK positively regulates inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) production in response to lipopolysaccharide (LPS). In TOPK-depleted cells, the iNOS expression was shown to be greatly abolished. Also, we revealed that LPS treatment augmented the expression and activity of TOPK, the interaction of TOPK with I kappa B alpha, and promoted TOPK kinase activity against I kappa B alpha. Moreover, NF-kappa B or iNOS promoter-driven transcriptional activity in response to LPS was markedly reduced by knocking down of TOPK or deletion of NF-kappa B sites. On the other hand, endogenous TOPK level was expressed very lowly in bone marrow-derived macrophage (BMDM) prepared from Toll-like receptor 4 (TLR4) knockout mice, compared to BMDM from wild type (WT) mice. Collectively, these findings demonstrate that TOPK upregulates iNOS gene expression in T cell leukemia Jurkat cells or macrophage leukemic Raw 264.7 cells via NF-kappa B activation in response to LPS, and might act as a critical effector in LPS/TLR4-mediated signaling cascade, suggesting a possible role of TOPK in inflammatory response or inflammation-related diseases. (c) 2014 Elsevier Inc. All rights reserved.