Anti-Inflammatory Effects of the Novel PIM Kinase Inhibitor KMU-470 in RAW 264.7 Cells through the TLR4-NF-κB-NLRP3 Pathway

• Published in: International journal of molecular sciences 2020-07, Vol.21 (14), p.5138
• Main Authors: Baek, Hye Suk, Min, Hyeon Ji, Hong, Victor Sukbong, Kwon, Taeg Kyu, Park, Jong Wook, Lee, Jinho, Kim, Shin
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Cytokines; Enzyme inhibitors; Gene regulation; IL-1β; Inflammasomes; Inflammatory bowel disease; Inflammatory diseases; Interleukin 6; Intermediates; Kinases; Lipopolysaccharides; Macrophages - drug effects; Macrophages - metabolism; Mice; MyD88 protein; NF-kappa B - metabolism; NF-κB protein; Nitric oxide; Nitric Oxide - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - metabolism; RAW 264.7 Cells; Serine; Signal transduction; Signal Transduction - drug effects; siRNA; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transcription; Transfection; Tumor necrosis factor-α
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21145138

PIM kinases, a small family of serine/threonine kinases, are important intermediates in the cytokine signaling pathway of inflammatory disease. In this study, we investigated whether the novel PIM kinase inhibitor KMU-470, a derivative of indolin-2-one, inhibits lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 cells. We demonstrated that KMU-470 suppressed the production of nitric oxide and inducible nitric oxide synthases that are induced by LPS in RAW 264.7 cells. Furthermore, KMU-470 inhibited LPS-induced up-regulation of TLR4 and MyD88, as well as the phosphorylation of IκB kinase and NF-κB in RAW 264.7 cells. Additionally, KMU-470 suppressed LPS-induced up-regulation at the transcriptional level of various pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6. Notably, KMU-470 inhibited LPS-induced up-regulation of a major component of the inflammasome complex, NLRP3, in RAW 264.7 cells. Importantly, PIM-1 siRNA transfection attenuated up-regulation of NLRP3 and pro-IL-1β in LPS-treated RAW 264.7 cells. Taken together, these findings indicate that PIM-1 plays a key role in inflammatory signaling and that KMU-470 is a potential anti-inflammatory agent.