Inhibition of Tumor Necrosis Factor-Alpha and lnterleukin-1-Beta Production by Beta-Adrenoceptor Agonists from Lipopolysaccharide- Stimulated Human Peripheral Blood Mononuclear Cells

Yoshimura, Tomoaki; Kurita, Chikako; Nagao, Tomomi; Usami, Eiseki; Nakao, Tomohiro; Watanabe, Shino; Kobayashi, J; Yamazaki, Futoshi; Tanaka, Hiroyuki; Inagaki, Nobuya; Nagai, Hiroichi

doi:10.1159/000139481

Cited by 71 publications

(35 citation statements)

References 17 publications

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“…In our experiments, bile acids induced cAMP production in rabbit AMs and THP-TGR5 cells. It has been known that an increase of intracellular cAMP results in the suppression of LPS-stimulated cytokine production in macrophages (23). We showed here that TGR5 was abundantly expressed in monocytes/macrophages and that bile acids including LCA, DCA, and CDCA inhibited LPS-stimulated TNF␣ secretion in rabbit AMs.…”

Section: Identification Of a Specific Gpcr For Bile Acids-in Searchinmentioning

confidence: 48%

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A G Protein-coupled Receptor Responsive to Bile Acids

Kawamata

Fujii

Hashimoto

et al. 2003

Journal of Biological Chemistry

1,345

1,388

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So far some nuclear receptors for bile acids have been identified. However, no cell surface receptor for bile acids has yet been reported. We found that a novel G protein-coupled receptor, TGR5, is responsive to bile acids as a cell-surface receptor. Bile acids specifically induced receptor internalization, the activation of extracellular signal-regulated kinase mitogen-activated protein kinase, the increase of guanosine 5-O-3-thiotriphosphate binding in membrane fractions, and intracellular cAMP production in Chinese hamster ovary cells expressing TGR5. Our quantitative analyses for TGR5 mRNA showed that it was abundantly expressed in monocytes/macrophages in human and rabbit. Treatment with bile acids was found to suppress the functions of rabbit alveolar macrophages including phagocytosis and lipopolysaccharide-stimulated cytokine productions. We prepared a monocytic cell line expressing TGR5 by transfecting a TGR5 cDNA into THP-1 cells that did not express TGR5 originally. Treatment with bile acids suppressed the cytokine productions in the THP-1 cells expressing TGR5, whereas it did not influence those in the original THP-1 cells, suggesting that TGR5 is implicated in the suppression of macrophage functions by bile acids.Bile acids are not simply byproducts of cholesterol metabolism but play essential roles in the absorption of dietary lipids and in the regulation of bile acid synthesis (1). Farnesoid X receptor and pregnane X receptor have been recently identified as specific nuclear receptors for bile acids (2-5). Through the activation of farnesoid X receptor bile acids repress the expression of cholesterol 7␣-hydroxylase, the rate-limiting enzyme in bile acid synthesis (2, 3). The activation of pregnane X receptor by bile acids results in both the repression of cholesterol 7␣-hydroxylase and the transcriptional induction of cytochrome P450 3a, the bile acid-metabolizing enzyme (4, 5). However, no cell surface receptor for bile acids has yet been identified. In hepatobiliary diseases including obstructive jaundice, viral hepatitis, and primary biliary cirrhosis, the mean serum concentration of bile acids exceeds 100 M (range, 70 -400 M), whereas normally this remains below 10 M (6). At such high concentrations, bile acids are known to exhibit immunosuppressive effects on cell-mediated immunity and macrophage functions (6 -8). The phagocytic capacity of the reticuloendothelial system including Kupffer cells is depressed in cholestasis or obstructive jaundice (8). Cholestatic jaundice frequently causes infectious complications and endotoxemia, which are closely related to elevated serum bile acid levels (7, 9). Furthermore, bile acids including deoxycholic acid (DCA) 1 and chenodeoxycholic acid (CDCA) have been demonstrated to have inhibitory activities on the lipopolysaccharide (LPS)-induced production of cytokines in macrophages, including interleukin (IL)-1, IL-6, and tumor necrosis factor ␣ (TNF␣) (10, 11). However, the precise mechanisms involved have remained unclear. Here we show that a novel G prot...

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Section: Identification Of a Specific Gpcr For Bile Acids-in Searchinmentioning

confidence: 48%

“…Analyses for Role of TGR5 in Macrophages-An increase of intracellular cAMP reportedly results in the suppression of LPS-stimulated cytokine production in macrophages (23). In addition, CD14 has been shown to function as the LPS receptor (24).…”

Section: Identification Of a Specific Gpcr For Bile Acids-in Searchinmentioning

confidence: 99%

A G Protein-coupled Receptor Responsive to Bile Acids

Kawamata

Fujii

Hashimoto

et al. 2003

Journal of Biological Chemistry

1,345

1,388

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“…It is also used to treat mild-to-moderate stress incontinence (Noguchi et al, 1997) and allergic inflammation (Yoshimura et al, 1997). However, clenbuterol is also abused by individuals that practice body building because of β2 agonists' anabolic effects and reduction of subcutaneous fat (Choo et al, 1992;Hesketh et al, 1992;Navegantes et al, 2001;Prather et al, 1995;Ryall et al, 2004;Yimlamai et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

β2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals

Ramos

Colgan

Nou

et al. 2008

Neurobiology of Aging

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Previous studies using a mixed β1 and β2 adrenergic antagonist, propanolol, have indicated that β adrenoceptors have little effect on the cognitive functioning of the prefrontal cortex. However, recent studies have suggested that endogenous stimulation of β1 adrenoceptors impairs working memory in both rats and monkeys. Since propanolol has no effect on cognition, we hypothesized that activation of β2 adrenoceptors might improve performance in a working memory task. We tested this hypothesis by observing the effects of the β2 agonist, clenbuterol, on spatial working memory performance. Clenbuterol was either infused directly into the prefrontal cortex (rats) or administered systemically (monkeys). Results demonstrated that clenbuterol improved performance in many young and aged rats and monkeys who performed poorly under control conditions. Actions at β2 adrenoceptors were confirmed by challenging the clenbuterol response with the β2 adrenergic antagonist, ICI 118,551. The effects of clenbuterol were not universal and depended on the cognitive status of the animal: the drug moderately improved only a subset of animals with working memory impairment.

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“…Attenuating excessive macrophage activation would be expected to be benefical in the treatment of respiratory diseases. Studies investigating the effects of -agonists on monocytes, monocyte-derived macrophages (MDM) and macrophagelike cell lines suggest that these drugs may modulate a number of macrophage functions including the prevention of pro-inflammatory cytokine generation (Yoshimura et al, 1997;Izeboud et al, 1999;Donnelly et al, 2010;Shirato et al, 2013). By contrast, other studies show limited effects of -agonists in these systems (Linden, 1992;Zetturlund et al, 1998;Ezeamuzie and Shihab, 2010).…”

Section: Introductionmentioning

confidence: 99%