Pro-inflammatory cytokines enhance dilatation of bile canaliculi caused by cholestatic antibiotics

Abstract

Many drugs can induce liver injury, characterized by hepatocellular, cholestatic or mixed hepatocellular-cholestatic lesions. While an inflammatory stress is known to aggravate hepatocellular injury caused by some drugs much less evidence exists for cholestatic features. In this study, the influence of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α), either individually or combined, on cytotoxic and cholestatic properties of antibiotics was evaluated using differentiated HepaRG cells. Six antibiotics of various chemical structures and known to cause cholestasis and/or hepatocellular injury in clinic were investigated. Caspase-3 activity was increased with all these tested hepatotoxic drugs and except with erythromycin, was further augmented in presence of cytokines mainly when these were co-added as a mixture. TNF-α and IL-1β aggravated cytotoxicity of TVX more than IL-6. Bile canaliculi (BC) dilatation induced by cholestatic drugs was increased by co-treatment with IL-6 and IL-1β but not with TNF-α. Reduced accumulation of carboxy-dichlorofluorescein, a substrate of the multi-drug resistance-associated protein 2, in antibiotic-induced dilatated BC, was further extended in presence of individual or mixed cytokines. In conclusion, our data demonstrate that pro-inflammatory cytokines either individually or in mixture, can modulate cholestatic and/or cytotoxic responses to antibiotics and that the extent of these effects is dependent on the cytokine and the cholestatic antibiotic.

Cell Membrane Transporters Facilitate the Accumulation of Hepatocellular Flucloxacillin Protein Adducts: Implication in Flucloxacillin-Induced Liver Injury

“…At high concentrations (>6 mM), cholestatic injury was evidenced by dilation of BC, reduced bile acid efflux, and secretion of hepatocyte proinflammatory cytokines such as IL-6 and IL-1β. 1,2,12 The alteration of BC morphology by flucloxacillin was further confirmed by the current study when a lower concentration of drug was used (1.5 mM). Flucloxacillin treatment of primary human hepatocytes was also associated with the release of high-mobility group box 1 protein and dendritic cells exposed to flucloxacillin-treated hepatocyte supernatant secreted TNFα, IL-6, and IL-1β.…”

Protective effects of catalpol on mitochondria of hepatocytes in cholestatic liver injury

“…The current findings also revealed that catalpol greatly reduced the contents of pro-inflammatory factors in the serum derived from model mice in a concentration-dependent manner. A recent study indicated that IL-6 and IL-1β may enhance the bile canaliculi dilatation caused by cholestatic antibiotics (36). It has also been found that ginsenoside can attenuate oxidative stress and the inflammatory response in rats with intrahepatic cholestasis (37).…”

The Role of Inflammation in Cholestatic Liver Injury

“…Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6 and IL-8, produced by the inflammatory cells, such as KCs and bile duct cells stimulated by LPS, can contribute to the development of cholestasis by inducing a sustained decrease in the levels of bile acid transport proteins. [97][98][99] In the early stages of inflammation, TNF-α and IL-1β are involved in the downregulation of NTCP, while in the later stages of inflammation, they are regulated by IL-6. 100,101 Higher levels of IL-8 may be associated with the development of PBC and reflect the progression of the disease towards cirrhosis.…”