IL-17A Synergistically Enhances Bile Acid–Induced Inflammation during Obstructive Cholestasis

Abstract

During obstructive cholestasis, increased concentrations of bile acids activate ERK1/2 in hepatocytes, which up-regulates early growth response factor 1, a key regulator of proinflammatory cytokines, such as macrophage inflammatory protein 2 (MIP-2), which, in turn, exacerbates cholestatic liver injury. Recent studies have indicated that IL-17A contributes to hepatic inflammation during obstructive cholestasis, suggesting that bile acids and IL-17A may interact to regulate hepatic inflammatory responses. We treated mice with an IL-17A neutralizing antibody or control IgG and subjected them to bile duct ligation. Neutralization of IL-17A prevented up-regulation of proinflammatory cytokines, hepatic neutrophil accumulation, and liver injury, indicating an important role for IL-17A in neutrophilic inflammation during cholestasis. Treatment of primary mouse hepatocytes with taurocholic acid (TCA) increased the expression of MIP-2. Co-treatment with IL-17A synergistically enhanced up-regulation of MIP-2 by TCA. In contrast to MIP-2, IL-17A did not affect up-regulation of Egr-1 by TCA, indicating that IL-17A does not affect bile acid-induced activation of signaling pathways upstream of early growth response factor 1. In addition, bile acids increased expression of IL-23, a key regulator of IL-17A production in hepatocytes in vitro and in vivo. Collectively, these data identify bile acids as novel triggers of the IL-23/IL-17A axis and suggest that IL-17A promotes hepatic inflammation during cholestasis by synergistically enhancing bile acid-induced production of proinflammatory cytokines by hepatocytes.

Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses

“…A bile acid mixture significantly increased the mRNA expression of pro-inflammatory cytokines in vitro in our study, which is consistent with results from a previous report [5] . TCA exhibited the highest increase after ANIT treatment in our study, and this factor increases the expression of MIP-2 in rodents and IL-8 in humans [6,7] . The reconstituted bile acid mixture markedly increased mKC and MIP-2 expression in vitro in our study, which is consistent with the results after ANIT administration in vivo.…”

“…One of the hypotheses regarding the pathophysiology of cholestasis is that accumulated hepatic bile acids directly induce cell apoptosis, as supported by studies on rat hepatocytes and human hepatoma lines [4,5] . Increasing attention has been paid the physiological role of bile acids acting as pro-inflammatory signals, which may trigger hepatic CXC chemokine formation during the development of cholestatic liver injury [6,7] . The abnormal circulation of bile acids partially reflects liver function [8] .…”

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

“…In rodents, levels of a-SMA and type I collagen, hallmarks of HSC activation, are increased in centrilobular lesions after a single dose of carbon tetrachloride [60]. Similarly in humans suffering from acute liver failure from viral hepatitis, drug toxicity, or autoimmune hepatitis, there is an increase in a-SMAexpressing cells within necrotic lesions indicating activation of HSCs [61].…”

Elevated red blood cell distribution width is associated with intrahepatic cholestasis of pregnancy

“…Recent studies demonstrated increased circulating levels of systemic and vascular inflammatory markers in pregnancies with ICP [12,14,15]. Systemic inflammation can be measured by a variety of serum markers and it is indicated that hematological indices and ratio of blood cell subtypes in CBC might have been used as an inflammatory marker in many diseases.…”

“…The exact pathogenesis of ICP is unknown but association between inflammation and disease has been previously reported in literature [7] .Elevated bile acid concentrations may lead to the release of several proinflammatory mediators and trigger inflammatory response in hepatocytes with infiltration of inflammatory cells into the liver [5,12,13]. The activated inflammatory cells cause significant liver injury [13] and liver's local intracellular response to inflammation determines the clinical outcome and prognosis of the disease [7].…”