Peer Reviewed

1

Document Type

Article

Publication Date

1-8-2016

Keywords

Gene Expression Regulation, Humans, Immunity, Mucosal, Immunosuppressive Agents, Interleukin-8, Lipopolysaccharides, Monocytes, NF-kappa B, Phosphorylation, Signal Transduction, TNF Receptor-Associated Factor 2, Tumor Necrosis Factor-alpha, U937 Cells, Ursodeoxycholic Acid

Comments

The original article is available at http://www.the-aps.org/

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.

Disciplines

Medical Molecular Biology | Medical Sciences

Citation

O'Dwyer AM, Lajczak NK, Keyes JA, Ward JB, Greene CM, Keely SJ.Ursodeoxycholic acid inhibits TNFα-induced IL-8 release from monocytes. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2018;311(2)334-41

PubMed ID

27340129

DOI Link

https://doi.org/10.1152/ajpgi.00406.2015

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

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