Ursodeoxycholic acid inhibits TNFα-induced IL-8 release from monocytes

Abstract

Monocytes are critical to the pathogenesis of inflammatory bowel disease (IBD) as they infiltrate the mucosa and release cytokines that drive the inflammatory response. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid with anti-inflammatory actions, has been proposed as a potential new therapy for IBD. However, its effects on monocyte function are not yet known. Primary monocytes from healthy volunteers or cultured U937 monocytes were treated with either the proinflammatory cytokine, TNFα (5 ng/ml) or the bacterial endotoxin, lipopolysaccharide (LPS; 1 μg/ml) for 24 h, in the absence or presence of UDCA (25-100 μM). IL-8 release into the supernatant was measured by ELISA. mRNA levels were quantified by qPCR and changes in cell signaling proteins were determined by Western blotting. Toxicity was assessed by measuring lactate dehydrogenase (LDH) release. UDCA treatment significantly attenuated TNFα-, but not LPS-driven, release of IL-8 from both primary and cultured monocytes. UDCA inhibition of TNFα-driven responses was associated with reduced IL-8 mRNA expression. Both TNFα and LPS stimulated NFκB activation in monocytes, while IL-8 release in response to both cytokines was attenuated by an NFκB inhibitor, BMS-345541. Interestingly, UDCA inhibited TNFα-, but not LPS-stimulated, NFκB activation. Finally, TNFα, but not LPS, induced phosphorylation of TNF receptor associated factor (TRAF2), while UDCA cotreatment attenuated this response. We conclude that UDCA specifically inhibits TNFα-induced IL-8 release from monocytes by inhibiting TRAF2 activation. Since such actions would serve to dampen mucosal immune responses in vivo, our data support the therapeutic potential of UDCA for IBD.

TLR4 interaction with LPS in glioma CD133+ cancer stem cells induces cell proliferation, resistance to chemotherapy and evasion from cytotoxic T lymphocyte-induced cytolysis

“…Consistent with our findings, LPS exposure induces release of IL-1β and IL-6 in U373-MG human astrocytoma cells [ 46 ]. LPS promotes the release of TNF-α and MIP-1α from monocytes [ 60 , 61 ], and TNF-α induces the release of IL-8 [ 62 , 63 ]. In lung cancer cells, LPS-triggered TLR4 activation enhances the secretion of IL-10 [ 64 ].…”

Bile Acid Signaling in Inflammatory Bowel Diseases

“…Because there are no GPBAR1 ligands currently under development, it is unclear whether or not the receptor mediates itching in humans. However, UDCA which we have shown to be a weak GPBAR1 ligand has been used to treat IBD and experimental data suggest a potential useful role for this agent in this setting [180][181][182][183][184][185]. Another potential complication of a GPBAR1 ligand could be diarrhea.…”

Liver Macrophages: Old Dogmas and New Insights

“…UDCA and 24-nor-UDCA have notably been shown to reduce liver inflammation in a Schistosomiasis mansoni cercariae infection model. (120) UDCA was also shown to reduce TNFα-induced IL-8 production by macrophages associated with a reduction in TNFα receptorassociated factor 2 (TRAF2) phosphorylation (121) and to reduce LPS-induced macrophage activation. (122)(123)(124) Although all cells in one organism possess the same genetic material, gene expression modulation through epigenetic modifications controlled by histone remodeling, transcription factors, miRNAs, and long noncoding RNAs results in a plethora of distinct cell types.…”