Nevirapine (NVP) can cause serious skin rashes and hepatotoxicity. It also causes an immune-mediated skin rash in rats but not hepatotoxicity. There is strong evidence that the rash is due to 12-hydroxynevirapine (12-OH-NVP), which is further metabolized to a reactive benzylic sulfate in the skin. This could both act as a hapten and induce a danger signal. In contrast, most of the covalent binding in the liver appears to involve oxidation of the methyl group leading to a reactive quinone methide. In this study we examined the effects of NVP and 12-OH-NVP on gene expression in the liver and skin. Both NVP and 12-OH-NVP induced changes in the liver, but the list of genes was different, presumably reflecting different bioactivation pathways. In contrast, many more genes were up-regulated in the skin by 12-OH-NVP than by NVP, which is consistent with the hypothesis that the 12-hydroxylation pathway is involved in causing the rash. Some genes up-regulated by 12-OH-NVP were Trim63, S100a7a, and IL22ra2, etc. Up-regulation of genes such as S100a7a, which is considered a danger signal, supports the danger hypothesis. Up-regulation of genes such as the ubiquitin ligase and Trim63 are consistent with protein-adduct formation. Up-regulation of IL-22ra2 gene suggests an immune response. These results provide important clues to how NVP causes induction of an immune response, in some cases leading to an idiosyncratic drug reaction.

Nevirapine (NVP) can cause serious skin rashes and hepatotoxicity. It also causes an immune-mediated skin rash in rats but not hepatotoxicity. There is strong evidence that the rash is due to 12-hydroxynevirapine (12-OH-NVP), which is further metabolized to a reactive benzylic sulfate in the skin. This could both act as a hapten and induce a danger signal. In contrast, most of the covalent binding in the liver appears to involve oxidation of the methyl group leading to a reactive quinone methide. In this study we examined the effects of NVP and 12-OH-NVP on gene expression in the liver and skin. Both NVP and 12-OH-NVP induced changes in the liver, but the list of genes was different, presumably reflecting different bioactivation pathways. In contrast, many more genes were up-regulated in the skin by 12-OH-NVP than by NVP, which is consistent with the hypothesis that the 12-hydroxylation pathway is involved in causing the rash. Some genes up-regulated by 12-OH-NVP were Trim63, S100a7a, and IL22ra2, etc. Up-regulation of genes such as S100a7a, which is considered a danger signal, supports the danger hypothesis. Up-regulation of genes such as the ubiquitin ligase and Trim63 are consistent with protein-adduct formation. Up-regulation of IL-22ra2 gene suggests an immune response. These results provide important clues to how NVP causes induction of an immune response, in some cases leading to an idiosyncratic drug reaction.

Chez la drosophile, l’activation du récepteur Toll menant à une réponse antimicrobienne peut se faire par deux voies différentes. Ces deux voies sont activées soit par des récepteurs dédiés, les Pattern Recognition Receptors (PRRs) reconnaissant des motifs moléculaires microbiens, soit par la coupure d’une molécule circulante appelée Perséphone par des protéases microbiennes extrêmement diverses sécrétées pendant une infection. Cependant, le mécanisme par lequel Perséphone est activée demeurait ambigu. Nous avons identifié une région unique dans Perséphone fonctionnant comme un appât pour les protéases exogènes indépendamment de leur origine, type ou spécificité. Une coupure dans cette région constitue la première étape d’une activation séquentielle de Perséphone ; elle permet de recruter la cathepsine circulante 26-29-p, qui va générer la forme active de Perséphone.Ces travaux montrent comment un récepteur de l’immunité innée, Perséphone, peut être activé par un signal de danger, en l’occurrence des enzymes microbiennes, et non par la détection de motifs moléculaires qui peuvent être présents dans la flore microbienne hébergée par les animaux. / In Drosophila, the antimicrobial response against infections can be triggered by two different extracellular mechanisms that both lead to the activation of the Toll receptor. These two mechanisms are activated either by the recognition of specific microbial determinants by Pattern Recognition Receptors (PRRs), or by the cleavage of the circulating serine protease Persephone by a wide range of microbial proteases secreted during infections. However, the molecular mechanism underlying Persephone activation remained ambiguous. We identified a unique region in Persephone pro-domain that functions as a bait for exogenous proteases independently of their origin, type or specificity. Cleavage of Persephone in this bait region constitutes the first step of a sequential activation and licenses the subsequent maturation of Persephone to the endogenous circulating cysteine cathepsin 26-29-p. Our data establish Persephone itself as an immune receptor able to sense a broad spectrum of microbes through the recognition of danger signals rather than molecular patterns.