Indirubin Inhibits LPS-Induced Inflammation via TLR4 Abrogation Mediated by the NF-kB and MAPK Signaling Pathways

• Published in: Inflammation Vol. 40; no. 1; pp. 1 - 12
• Main Authors: Lai, Jin-lun, Liu, Yu-hui, Liu, Chang, Qi, Ming-pu, Liu, Rui-ning, Zhu, Xi-fang, Zhou, Qiu-ge, Chen, Ying-yu, Guo, Ai-zhen, Hu, Chang-min
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2017; Springer Nature B.V
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cytokines - drug effects; Cytokines - metabolism; Dose-Response Relationship, Drug; Female; Immunology; Indoles - pharmacology; Indoles - therapeutic use; Inflammation - drug therapy; Inflammation Mediators - metabolism; Internal Medicine; Lipopolysaccharides; MAP Kinase Signaling System - drug effects; Mastitis - drug therapy; Mice; NF-kappa B - metabolism; Original Article; Pathology; Pharmacology/Toxicology; Rheumatology; Signal Transduction - drug effects; Toll-Like Receptor 4 - physiology; indirubin; lipopolysaccharide (LPS); MAPK; inflammation; TLR4; NF-kB
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-016-0447-7

Indirubin plays an important role in the treatment of many chronic diseases and exhibits strong anti-inflammatory activity. However, the molecular mode of action during mastitis prophylaxis remains poorly understood. In this study, a lipopolysaccharide (LPS)-induced mastitis mouse model showed that indirubin attenuated histopathological changes in the mammary gland, local tissue necrosis, and neutrophil infiltration. Moreover, indirubin significantly downregulated the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). We explored the mechanism whereby indirubin exerts protective effects against LPS-induced inflammation of mouse mammary epithelial cells (MMECs). The addition of different concentrations of indirubin before exposure of cells to LPS for 1 h significantly attenuated inflammation and reduced the concentrations of the three inflammatory cytokines in a dose-dependent manner. Indirubin downregulated LPS-induced cyclooxygenase-2 (COX-2) and Toll-like receptor 4 (TLR4) expression, inhibited phosphorylation of the LPS-induced nuclear transcription factor-kappa B (NF-kB) P65 protein and its inhibitor IkBα of the NF-kB signaling pathway. Furthermore, indirubin suppressed phosphorylation of P38, extracellular signal-regulated kinase (ERK), and c-Jun NH 2 -terminal kinase (JNK) of the mitogen-activated protein kinase (MAPK) signal pathways. Thus, indirubin effectively suppressed LPS-induced inflammation via TLR4 abrogation mediated by the NF-kB and MAPK signaling pathways and may be useful for mastitis prophylaxis.