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

Ahmad Sharanek (1) , Audrey Burban (1) , Nadia Ciriaci (1) , André Guillouzo (1)

1 NuMeCan - Nutrition, Métabolismes et Cancer

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.

Mots clés: Inflammatory stress; HepaRG cells; Bile canaliculi; Canalicular efflux; Cholestasis; Drug-induced liver injury

Domaines: Sciences du Vivant [q-bio]; Toxicologie

Ahmad Sharanek, Audrey Burban, Nadia Ciriaci, André Guillouzo. Pro-inflammatory cytokines enhance dilatation of bile canaliculi caused by cholestatic antibiotics. Toxicology in Vitro, 2019, 58, pp.51-59. ⟨10.1016/j.tiv.2019.03.015⟩. ⟨hal-02087902⟩