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Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice.

Kim KH, Sung HJ, Lee WR, An HJ, Kim JY, Pak SC, Han SM, Park KK - Toxins (Basel) (2015)

Bottom Line: In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis.DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis.Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, College of Medicine, Catholic University of Daegu, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu 705-718, Korea. khkim1@cu.ac.kr.

ABSTRACT
Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

No MeSH data available.


Related in: MedlinePlus

Melittin inhibits pro-inflammatory cytokine expression in DDC-fed mice. (A) Western blotting results demonstrated that melittin effectively suppresses the expressions of TNF-α, IL-6 and p-STAT3; (B) graphical presentation of the ratio of TNF-α, IL-6 and p-STAT3 to GAPDH in various groups. NC, normal control group; Mel, melittin (0.1 mg/kg)-treated group with normal diet; DDC, 0.1% DDC-supplemented diet group; DDC + Mel, melittin (0.1 mg/kg)-treated group with 0.1% DDC-supplemented diet. Results are expressed as the mean ± SE of three independent determinations. *p < 0.05 compared to the NC group. †p < 0.05 compared to the Mel group. ‡p < 0.05 compared to the DDC group.
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toxins-07-03372-f004: Melittin inhibits pro-inflammatory cytokine expression in DDC-fed mice. (A) Western blotting results demonstrated that melittin effectively suppresses the expressions of TNF-α, IL-6 and p-STAT3; (B) graphical presentation of the ratio of TNF-α, IL-6 and p-STAT3 to GAPDH in various groups. NC, normal control group; Mel, melittin (0.1 mg/kg)-treated group with normal diet; DDC, 0.1% DDC-supplemented diet group; DDC + Mel, melittin (0.1 mg/kg)-treated group with 0.1% DDC-supplemented diet. Results are expressed as the mean ± SE of three independent determinations. *p < 0.05 compared to the NC group. †p < 0.05 compared to the Mel group. ‡p < 0.05 compared to the DDC group.

Mentions: DDC-fed mice demonstrated pronounced hepatic inflammatory response characterized by an increase of infiltrating inflammatory cells near bile ducts (Figure 1C). In contrast, treatment with melittin changed the inflammatory response in portal tracts (Figure 1D). To investigate whether melittin could influence inflammatory changes in DDC-fed mice, pro-inflammatory cytokines were examined in the livers of experimental mice. Pro-inflammatory cytokines, such as TNF-α and IL-6, are key players in eliciting an inflammatory reaction during liver fibrogenesis [13,14]. The expressions of TNF-α and IL-6 were significantly increased in the DDC-fed mice, whereas melittin treatment markedly abrogated this activation (Figure 4). During liver injury, IL-6 activates STAT3 in liver parenchymal and non-parenchymal cells [15,16]. While chronic DDC feeding activated p-STAT3 in the DDC group, the expression level of p-STAT3 was significantly reduced by treatment with melittin. Moreover, the expression level of MCP-1, which promotes liver fibrosis by recruitment of macrophages, was determined by immunohistochemical staining. As shown in Figure 5A,B, MCP-1-positive cells were barely detected in liver sections from the NC and Mel groups. However, MCP-1-positive areas in the DDC group were significantly increased in liver sections, especially near portal tracts (Figure 5C). Compared to the DDC group, treatment with melittin inhibited MCP-1 expression in DDC + Mel liver (Figure 5D). These results indicate that melittin markedly attenuates the levels of pro-inflammatory cytokines during chronic DDC feeding, which may result in the suppression of DDC-induced cholangitis.


Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice.

Kim KH, Sung HJ, Lee WR, An HJ, Kim JY, Pak SC, Han SM, Park KK - Toxins (Basel) (2015)

Melittin inhibits pro-inflammatory cytokine expression in DDC-fed mice. (A) Western blotting results demonstrated that melittin effectively suppresses the expressions of TNF-α, IL-6 and p-STAT3; (B) graphical presentation of the ratio of TNF-α, IL-6 and p-STAT3 to GAPDH in various groups. NC, normal control group; Mel, melittin (0.1 mg/kg)-treated group with normal diet; DDC, 0.1% DDC-supplemented diet group; DDC + Mel, melittin (0.1 mg/kg)-treated group with 0.1% DDC-supplemented diet. Results are expressed as the mean ± SE of three independent determinations. *p < 0.05 compared to the NC group. †p < 0.05 compared to the Mel group. ‡p < 0.05 compared to the DDC group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591642&req=5

toxins-07-03372-f004: Melittin inhibits pro-inflammatory cytokine expression in DDC-fed mice. (A) Western blotting results demonstrated that melittin effectively suppresses the expressions of TNF-α, IL-6 and p-STAT3; (B) graphical presentation of the ratio of TNF-α, IL-6 and p-STAT3 to GAPDH in various groups. NC, normal control group; Mel, melittin (0.1 mg/kg)-treated group with normal diet; DDC, 0.1% DDC-supplemented diet group; DDC + Mel, melittin (0.1 mg/kg)-treated group with 0.1% DDC-supplemented diet. Results are expressed as the mean ± SE of three independent determinations. *p < 0.05 compared to the NC group. †p < 0.05 compared to the Mel group. ‡p < 0.05 compared to the DDC group.
Mentions: DDC-fed mice demonstrated pronounced hepatic inflammatory response characterized by an increase of infiltrating inflammatory cells near bile ducts (Figure 1C). In contrast, treatment with melittin changed the inflammatory response in portal tracts (Figure 1D). To investigate whether melittin could influence inflammatory changes in DDC-fed mice, pro-inflammatory cytokines were examined in the livers of experimental mice. Pro-inflammatory cytokines, such as TNF-α and IL-6, are key players in eliciting an inflammatory reaction during liver fibrogenesis [13,14]. The expressions of TNF-α and IL-6 were significantly increased in the DDC-fed mice, whereas melittin treatment markedly abrogated this activation (Figure 4). During liver injury, IL-6 activates STAT3 in liver parenchymal and non-parenchymal cells [15,16]. While chronic DDC feeding activated p-STAT3 in the DDC group, the expression level of p-STAT3 was significantly reduced by treatment with melittin. Moreover, the expression level of MCP-1, which promotes liver fibrosis by recruitment of macrophages, was determined by immunohistochemical staining. As shown in Figure 5A,B, MCP-1-positive cells were barely detected in liver sections from the NC and Mel groups. However, MCP-1-positive areas in the DDC group were significantly increased in liver sections, especially near portal tracts (Figure 5C). Compared to the DDC group, treatment with melittin inhibited MCP-1 expression in DDC + Mel liver (Figure 5D). These results indicate that melittin markedly attenuates the levels of pro-inflammatory cytokines during chronic DDC feeding, which may result in the suppression of DDC-induced cholangitis.

Bottom Line: In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis.DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis.Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, College of Medicine, Catholic University of Daegu, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu 705-718, Korea. khkim1@cu.ac.kr.

ABSTRACT
Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

No MeSH data available.


Related in: MedlinePlus