Activation of lipopolysaccharide-TLR4 signaling accelerates the ototoxic potential of cisplatin in mice.

Abstract

Dysfunction in immune surveillance during anticancer chemotherapy of patients often causes weakness of the host defense system and a subsequent increase in microbial infections. However, the deterioration of organ-specific function related to microbial challenges in cisplatin-treated patients has not yet been elucidated. In this study, we investigated cisplatin-induced TLR4 expression and its binding to LPS in mouse cochlear tissues and the effect of this interaction on hearing function. Cisplatin increased the transcriptional and translational expression of TLR4 in the cochlear tissues, organ of Corti explants, and HEI-OC1 cells. Furthermore, cisplatin increased the interaction between TLR4 and its microbial ligand LPS, thereby upregulating the production of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, via NF-κB activation. In C57BL/6 mice, the combined injection of cisplatin and LPS caused severe hearing impairment compared with that in the control, cisplatin-alone, or LPS-alone groups, whereas this hearing dysfunction was completely suppressed in both TLR4 mutant and knockout mice. These results suggest that hearing function can be easily damaged by increased TLR expression and microbial infections due to the weakened host defense systems of cancer patients receiving therapy comprising three to six cycles of cisplatin alone or cisplatin combined with other chemotherapeutic agents. Moreover, such damage can occur even though patients may not experience ototoxic levels of cumulative cisplatin concentration.

• Authors: Gi-Su Oh, Hyung-Jin Kim, Jae-Hyuck Choi, AiHua Shen, Chang-Hoi Kim, Se-Jin Kim, Sae-Ron Shin, Seung-Heon Hong, Yunha Kim, Channy Park, Sung-Joong Lee, Shizuo Akira, Raekil Park, Hong-Seob So
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 186 Issue 2 Pg. 1140-50 (Jan 15 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21148032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Ligands
• Lipopolysaccharides
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (administration & dosage, toxicity)
• Cell Line, Transformed
• Cisplatin (administration & dosage, toxicity)
• Ligands
• Lipopolysaccharides (metabolism, physiology)
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Knockout
• Organ Culture Techniques
• Organ of Corti (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)
• Time Factors
• Toll-Like Receptor 4 (deficiency, metabolism, physiology)