Bile acids with differing hydrophilic-hydrophobic properties do not influence cytokine production by human monocytes and murine Kupffer cells

Abstract

conclusion, bile acids with widely different hydrophobiBile acids have been proposed to exert immunological cities are incapable of influencing the release of IL-6 and effects of potential pathogenic or therapeutic relevance, TNFa by monocytes and Kupffer cells, provided they are yet the experimental evidence remains preliminary. We studied at noncytotoxic concentrations and in the presreexamined the effects of a variety of bile salts with difence of physiological amounts of proteins. (HEPATOLOGY fering hydrophilic-hydrophobic properties on the pro-1997;25:927-933.) duction of interleukin-6 (IL-6) and tumor necrosis factor a (TNFa) from monocytes and Kupffer cells. Monocytes from healthy human donors and Kupffer cells from 5-Infectious complications 1,2 and endotoxemia 3,4 occur freweek-old mice were incubated for up to 18 hours with quently in patients with severe cholestasis. The underlying or without varying concentrations of bile salts and lipo-mechanisms are not fully understood, yet cholestasis may be polysaccharide (LPS). Monocyte viability was ¢95% with the consequence of the impairment of cell-mediated immuup to 250 mmol/L sodium ursodeoxycholate and°90% nity 5-7 and macrophage function. 8 Endotoxins are lipopolysacwith 200 mmol/L chenodeoxycholate, decreasing sharply charides (LPS) present in the wall of gram-negative bacteria. at higher concentrations. Kupffer cells were more vul-Endotoxemia may derive from both systemic infections with nerable, particularly to chenodeoxycholate (viabilities gram-negative bacteria or from absorption of LPS from the of 25% and 0% at concentrations of 100 mmol/L and 200 gut. Normally, LPS is cleared by liver macrophages (Kupffer mmol/L, respectively). In monocytes incubated in the cells), but when their phagocytic function is impaired, as in presence of 20% fetal calf serum, neither ursodeoxycho-cholestasis, or an excessive amount of LPS is being delivered late and chenodeoxycholate, nor a variety of other un-from the intestine, endotoxins may spill over into the periphconjugated and conjugated bile acids, tested up to their eral circulation. LPS stimulates both circulating and tissue maximal noncytotoxic concentrations, influenced the macrophages to release several cytokines, 9,10 known to be po-IL-6 and TNFa production, at any level of LPS stimula-tent inflammatory mediators, 11 as well as activators of a comtion. Similar to monocytes, incubation of murine Kupffer plex immuno-metabolic cascade, 12-14 mimicking the effects of cells with ursodeoxycholate and chenodeoxycholate did acute infections. 15 This establishes a vicious cycle, aggravatnot influence cytokine release. In contrast, the addition ing the original cholestasis and often leading to multiple orof 10 nmol/L dexamethasone to monocytes significantly gan failure. On the other hand, during bacterial sepsis, the decreased TNF-a and IL-6 release (69 { 11% and 48 { liver is the main organ responsive to LPS, 16 presumably be-15%, respectively). When monocytes were incubated cause Kupffer cells are the major source...

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

“…In vitro studies suggested direct immunomodulating effects of UDCA on cytokine secretion of peripheral monocytes; the physiologic relevance of these studies, however, has been questioned due to methodological concerns. 41 …”

Characterization of chenodeoxycholic acid as an endogenous antagonist of the G-coupled formyl peptide receptors

“…Earlier studies showed that some bile acids, particularly chenodeoxycholic acid (CDCA) one of two major human primary bile acids, possessed immunosuppressive properties [16 -20] including inhibiting the production of IL-1, IL-6 and TNF-a by monocytes [21,22]. While regulation of cytokine gene expression by the CDCA nuclear receptor may contribute to immunosuppression [23], we considered it likely that interference with fMLP receptors might also contribute to the immune suppressive effects of bile acids [4,24,25].…”

Ursodeoxycholic Acid but Not Tauroursodeoxycholic Acid Inhibits Proliferation and Differentiation of Human Subcutaneous Adipocytes

“…The effective concentrations of BAs were based on previously published observations [14,15]. To create ERS, cells were treated with 1 mg/ml tunicamycin (LKT Laboratories, St. Paul, MN, USA).…”