Perturbation in the cytokine network is correlated with

Perturbation in the cytokine network is correlated with disruption of growth hormone and glucocorticoid (GC) homeostasis (Thissen and Verniers, 1997; Sahid El-Radhi et al., 2000; Waxman and Holloway, 2009; Zhao et al., 2014), with important physiological consequences because cytokines affect the regulation of multiple signal transduction cascades (signaling pathways), such as the mitogen-activated protein kinase (ERK1/2) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways, which play important roles in controlling the a83 01 australia of CYP isoforms by regulating the transcriptional activity of nuclear receptors (Morgan, 1997, 2001; Pascussi et al., 2008; Waxman and Holloway, 2009; Gerbal-Chaloin et al., 2013). Our recent study proved that dysfunction of the peripheral serotonergic system during liver insufficiency results in upregulation of AhR target genes by activating the mitogen-activated protein kinase pathway (Kot and Daujat-Chavanieu, 2016). However, dysfunction in the peripheral serotonergic system also influences the activity and levels of the CYP2C11 and CYP3A proteins in the rat liver (Kot and Daniel, 2011; Kot et al., 2012; Kot, 2015). Therefore, the aim of this study is to investigate a potential mechanism by which the serotonergic system can control the expression and activity of the CYP2C11 and CYP3A isoforms during liver insufficiency. Liver insufficiency was induced by the administration of diethylnitrosamine (DEN), an environmental liver carcinogen (Fine et al., 1977) that is frequently used to generate liver insufficiency during chemically induced hepatocarcinogenesis in rats (Lim, 2003). Serotonergic system dysfunction was induced by feeding the rats with a diet lacking tryptophan, a simple, noninvasive, effective and very specific method of reducing serum serotonin (Culley et al., 1963; Culafic et al., 2007; Kot et al., 2012; Kot and Daujat-Chavanieu, 2016).
Materials and methods
Results
Discussion and conclusions Our previous study showed that dysfunction of the serotonergic system leads to upregulation of AhR target genes and their protein levels and activity during liver insufficiency (Kot and Daujat-Chavanieu, 2016). Here, for the first time, a link between the altered immune stimuli during liver insufficiency and the subsequent changes in the expression and activity of CYP2C11 and CYP3A1/2 isoforms mediated by the JAK1/STAT6/SOCS-1 and ERK1/2 pathways under the control of the serotonergic system is demonstrated. In addition, a potential role for testosterone in regulating the expression of these CYP isoforms under control of the serotonergic system is highlighted. In the present study, chronic DEN administration evoked liver insufficiency, as confirmed by H&E staining of liver sections, a decrease in total body weight, an increased liver/body weight ratio, and significant elevation of serum levels of alpha-fetoprotein (AFP), alpha (2) macroglobulin (M2G), the noninvasive markers of liver insufficiency aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and albumin gene expression. Moreover, DEN-evoked liver insufficiency was positively correlated with a significantly increased TGF-β level, which led to an increased serum serotonin level, due to its release from activated platelets. Consistent with this interpretation, previous studies have shown that TGF-β stimulates collagen production, which is required for collagen-induced platelet aggregation and activation, whereas serotonin is released from activated platelets, which are the main storage site of peripheral serotonin (Meyer et al., 1990; Leask and Abraham, 2004; Ruddell et al., 2008; Shajib and Khan, 2015). Due to the lack of a precursor for serotonin, a tryptophan-deficient diet for 3 weeks led to a reduced serum serotonin level and confirmed the successful dysregulation of the peripheral serotonergic system during normal liver function and during liver insufficiency. Concomitant reductions in the levels of the 5-HT1B and PKA proteins in response to serotonergic system dysfunction during liver insufficiency suggest that the 5-HT1B receptor is directly stimulated by serum serotonin. Specifically, one important mechanism that regulates 5-HT1B receptor function and is negatively correlated with PKA signaling is receptor desensitization and internalization following serotonin-induced activation (Barnes and Sharp, 1999). However, the serum serotonin level after serotonergic system dysfunction during liver insufficiency was only slightly but significantly increased compared to that in rats after induced serotonergic system dysfunction during normal liver function. One possible explanation for this is the release of serotonin from minor reserves of peripheral serotonin, such as lymphocytes, monocytes, macrophages, and mast cells, which can stimulate the 5-HT1B receptor.