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

• Autores: Sharanek, Ahmad; Burban, Audrey; Ciriaci, Nadia; Guillouzo, André
• Año de publicación: 2019
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: BILE CANALICULI; CANALICULAR EFFLUX; CHOLESTASIS; DRUG-INDUCED LIVER INJURY; HEPARG CELLS; INFLAMMATORY STRESS
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Sharanek, Ahmad. Institut National de la Recherche Agronomique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Rennes; Francia
Fil: Burban, Audrey. Institut National de la Recherche Agronomique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Rennes; Francia
Fil: Ciriaci, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. Institut National de la Santé et de la Recherche Médicale; Francia. Institut National de la Recherche Agronomique; Francia. Universite de Rennes; Francia
Fil: Guillouzo, André. Institut National de la Recherche Agronomique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Rennes; Francia