Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages

Abstract

That cholestatic conditions are accompanied by an enhanced susceptibility to bacterial infection in human and animal models is a known phenomenon. This correlates with the observation that bile acids have suppressive effects on cells of innate and adaptive immunity. The present study provides evidence that in human macrophages, bile acids inhibit the LPS-induced expression of proinflammatory cytokines without affecting the expression of the anti-inflammatory cytokine IL-10. This results in a macrophage phenotype that is characterized by an increased IL-10/IL-12 ratio. Correspondingly, bile acids suppress basal phagocytic activity of human macrophages. These effects of bile acids can be mimicked by cAMP, which is presumably induced TGR5-dependently. The data provided further suggest that in primary human macrophages, modulation of the macrophage response toward LPS by bile acids involves activation of CREB, disturbed nuclear translocation of NF-κB, and PKA-dependent enhancement of LPS-induced cFos expression. The increase in cFos expression is paralleled by an enhanced formation of a protein complex comprising cFos and the p65 subunit of NF-κB. In summary, the data provided suggest that in human macrophages, bile acids induce an anti-inflammatory phenotype characterized by an increased IL-10/IL-12 ratio via activation of PKA and thereby, prevent their activation as classically activated macrophages. This bile acid-induced modulation of macrophage function may also be responsible for the experimentally and clinically observed anti-inflammatory and immunosuppressive effects of bile acids.

TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation

“…As the b-ZIP domain of LAP has been reported to interact with the Rel homology domain of NF-κB and to enhance NF-κB-dependent transcription (82)(83)(84)(85), the dominant-negative C/EBPβ isoform LIP could also blunt NF-κB activation and further decrease the inflammatory response. Several studies demonstrate that TGR5 activation inhibits NF-κB signaling through pleiotropic mechanisms, including IκBα, CREB, and c-Fos phosphorylation (32,34,36). Our present data add modulation of LIP translation to the means by which TGR5 could reduce the inflammatory actions of NF-κB.…”

“…TGR5 is also expressed in cells of the hematopoietic system, such as monocytes and macrophages, and confers potent antiinflammatory properties in vitro and in vivo (31)(32)(33)(34)(35)(36). Recent work from our laboratory revealed that the immune-suppressive actions of TGR5 in macrophages contribute to the prevention of the atherosclerotic process (34).…”

G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a KCa1.1 (BKCa)–Dependent Mechanism

“…Moreover, effects in dog occurred at concentrations overlapping with the IC 50 values for inhibition of human TNF-a and IL-12p40 production (in vitro functional indices of efficacy) and, for BIX02694, at near-therapeutic concentrations in a preclinical DNBS efficacy model suggesting an inability to separate GPBAR1-mediated efficacy and ontarget cardiovascular liabilities in vivo and that resulted in termination of the project. GPBAR1 signaling in myeloid cells leads to downregulation of responses to proinflammatory stimuli in primary human macrophages in vitro (Haselow et al, 2013;Yoneno et al, 2013) and reductions in inflammation in vivo via genetic approaches in which knockout mice are more susceptible to inflammation (Wang et al, 2011), including injury-induced colitis (Cipriani et al, 2011), or in which receptor agonists offer protection from colitis and other inflammatory models (Martín et al, 2010;Cipriani et al, 2011;Pols et al, 2011a). In colitis, the improvement in the clinical score appears to be linked to a direct impact on monocyte infiltration into the colon, consistent with the importance of these cells in disease pathology.…”

Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes

“…Gastrointestinal and hepatotrophic viruses replicate in the presence of bile acids that influence cellular signaling, innate and adaptive immune responses (22,29,30), and interferon (IFN) signaling (31). Hepatitis C virus (HCV) and hepatitis B virus (HBV) benefit from bile acid-dependent FXR activation (32,33), while for rotaviruses a significantly reduced fecal shedding was shown at 1 and 3 days postinfection in chenodeoxycholic acid-fed mice (34).…”