Regulatory role of the TLR4/JNK signaling pathway in sepsis-induced myocardial dysfunction

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and is a leading cause of mortality worldwide. Myocardial dysfunction is associated with poor prognosis in patients with sepsis and contributes to a high risk of mortality. However, the pathophysiological mechanisms underlying sepsis-induced myocardial dysfunction are not completely understood. The aim of the present study was to investigate the role of toll-like receptor 4 (TLR4)/c-Jun N-terminal kinase (JNK) signaling in pro-inflammatory cytokine expression and cardiac dysfunction during lipopolysaccharide (LPS)-induced sepsis in mice. C57BL/6 mice were pretreated with TAK-242 or saline for 1 h and then subjected to LPS (12 mg/kg, intraperitoneal) treatment. Cardiac function was assessed using an echocardiogram. The morphological changes of the myocardium were examined by hematoxylin and eosin staining and transmission electron microscopy. The serum protein levels of cardiac troponin I (cTnI) and tumor necrosis factor-α (TNF-α) were determined by an enzyme-linked immunosorbent assay (ELISA). The TLR4 and JNK mRNA levels were analyzed via reverse transcription-quantitative PCR. TLR4, JNK and phosphorylated-JNK protein levels were measured by western blotting. In response to LPS, the activation of TLR4 and JNK in the myocardium was upregulated. There were significant increases in the serum levels of TNF-α and cTnI, as well as histopathological changes in the myocardium and suppressed cardiac function, following LPS stimulation. Inhibition of TLR4 activation using TAK-242 led to a decrease in the activation of JNK and reduced the protein expression of TNF-α in plasma, and alleviated histological myocardial injury and improved cardiac function during sepsis in mice. The present data suggested that the TLR4/JNK signaling pathway played a critical role in regulating the production of pro-inflammatory cytokines and myocardial dysfunction induced by LPS.