Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 533, Issue 4, Pages 1290-1297Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2020.10.007
Keywords
With-no-lysine kinase; TGF beta-activated kinase 1; Macrophage; Cytokine; Lipopolysaccharide; Sepsis
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Funding
- Japan Society of the Promotion of Science (JSPS) [25221306-00, 19H01049, 18K19534, 16H05314, 19H03672, 19K16686]
- Ministry of Health Labor and Welfare, AMED [JP18ek0109304]
- Salt Science Research Foundation
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With-no-lysine kinase (WNK) plays important roles in regulating electrolyte homeostasis, cell signaling, survival, and proliferation. It has been recently demonstrated that WNK1, a member of the WNK family, modifies the function of immune cells. Here we report that in macrophages, WNK1 has suppressive effects on lipopolysaccharide (LPS)-induced inflammatory responses via TGFB-activated kinase 1 (TAK1)mediated activation of nuclear factor-kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) signaling pathway. We found that WNK1 heterozygous (WNK1(+/-)) mice produced excessive proinflammatory cytokines in an experimental LPS-induced sepsis model, and peritoneal macrophages isolated from WNK1(+/-) mice produced higher levels of LPS-induced cytokines and NOS2 expression as canonical proinflammatory M1 macrophage markers. We confirmed that small hairpin RNA (shRNA)mediated knockdown of WNK1 activated LPS-induced cytokine production and NOS2 expression in RAW 264.7 macrophages. Moreover, we demonstrated that WNK1 knockdown increased the nuclear trans location of NF-kappa B and activated the p38 and Jun N-terminal kinase (JNK) MAPK signaling pathway and that a TAK1 inhibitor diminished these effects of WNK1 knockdown. These results suggest that WNK1 acts as a physiologic immune modulator via interactions with TAK1. WNK1 may be a therapeutic target against the cytokine storm caused by sepsis. (C) 2020 Elsevier Inc. All rights reserved.
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