Kupffer cell-mediated exacerbation of methimazole-induced acute liver injury in rats
| Autor: | Sho Akai, Koichi Tsuneyama, Shingo Oda, Tsuyoshi Yokoi, Yasuaki Uematsu |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Liver injury MAPK/ERK pathway medicine.medical_specialty Innate immune system Kinase business.industry Kupffer cell Toxicology medicine.disease 03 medical and health sciences 030104 developmental biology Endocrinology medicine.anatomical_structure Immune system Internal medicine medicine TLR4 business Receptor |
| Zdroj: | Journal of Applied Toxicology. 36:702-715 |
| ISSN: | 0260-437X |
| DOI: | 10.1002/jat.3202 |
| Popis: | Methimazole (MTZ), an anti-thyroid drug, is known to cause liver injury in humans. It has been demonstrated that MTZ-induced liver injury in Balb/c mice is accompanied by T helper (Th) 2 cytokine-mediated immune responses; however, there is little evidence for immune responses associated with MTZ-induced liver injury in rats. To investigate species differences in MTZ-induced liver injury, we administered MTZ with a glutathione biosynthesis inhibitor, L-buthionine-S,R-sulfoximine (BSO), to F344 rats and subsequently observed an increase in plasma alanine aminotransferase (ALT) and high-mobility group box 1 (HMGB1), which are associated with hepatic lesions. The hepatic mRNA expression of innate immune-related genes significantly increased in BSO- and MTZ-treated rats, but the change in Th2-related genes was not much greater than the change observed in the previous mouse study. Moreover, an increase in Kupffer cells and an induction of the phosphorylation of extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK) proteins were accompanied by an increase in Toll-like receptor 4 (TLR4) expression, indicating that Kupffer cell activation occurs through HMGB1-TLR4 signaling. To elucidate the mechanism of liver injury in rats, gadolinium chloride, which inactivates the function of Kupffer cells, was administered before BSO and MTZ administration. The gadolinium chloride treatment significantly suppressed the increased ALT, which was accompanied by decreased hepatic mRNA expression related to innate immune responses and ERK/JNK phosphorylation. In conclusion, Kupffer cell-mediated immune responses are crucial factors for the exacerbation of MTZ-induced liver injury in rats, indicating apparent species differences in the immune-mediated exacerbation of liver injury between mice and rats. Copyright © 2015 John Wiley & Sons, Ltd. |
| Databáze: | OpenAIRE |
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