WNK1-TAK1 signaling suppresses lipopolysaccharide-induced cytokine production and classical activation in macrophages.

Abstract

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 TGFβ-activated kinase 1 (TAK1)-mediated activation of nuclear factor-kappa B (NF-κB) 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 translocation of NF-κB 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.

• Authors: Yohei Arai, Kenichi Asano, Shintaro Mandai, Fumiaki Ando, Koichiro Susa, Takayasu Mori, Naohiro Nomura, Tatemitsu Rai, Masato Tanaka, Shinichi Uchida, Eisei Sohara
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 533 Issue 4 Pg. 1290-1297 (12 17 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 33046244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Lipopolysaccharides
• NF-kappa B
• WNK Lysine-Deficient Protein Kinase 1
• Wnk1 protein, mouse
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Animals
• Cells, Cultured
• Cytokines (biosynthesis)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lipopolysaccharides
• MAP Kinase Kinase Kinases (metabolism, physiology)
• MAP Kinase Signaling System
• Macrophage Activation
• Macrophages (drug effects, enzymology, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• RAW 264.7 Cells
• Sepsis (chemically induced, enzymology, immunology)
• WNK Lysine-Deficient Protein Kinase 1 (genetics, metabolism, physiology)
• p38 Mitogen-Activated Protein Kinases (metabolism)