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Downregulation of OATP2B1 by proinflammatory cytokines leads to 5-ASA hyposensitivity in Ulcerative colitis.
- Source :
-
Chemico-Biological Interactions . Aug2024, Vol. 398, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
Abstract
- 5-Aminosalicylic acid (5-ASA) is a first-line agent in both remission and maintenance therapy for ulcerative colitis (UC). However, the mucosal concentration of 5-ASA was significantly lower in patients with severe histological inflammation, which further led to a poor response to 5-ASA treatment. Our study aimed to clarify the mechanism of 5-ASA uptake into colonic epithelial cells and to further explore the reason for the decreased colonic mucosal 5-ASA concentration in UC patients. Our results demonstrated that the colonic 5-ASA concentration was notably reduced in DSS-induced colitis mice and inversely correlated with colonic inflammation. 5-ASA was not a substrate of carnitine/organic cation transporter 1/2 (OCTN1/2) or multidrug resistance protein 1 (MDR1), whereas organic anion transporting polypeptide 2B1 (OATP2B1) and sodium-coupled monocarboxylate transporter 1 (SMCT1) mediated the uptake of 5-ASA, with a greater contribution from OATP2B1 than SMCT1. Inhibitors and siRNAs targeting OATP2B1 significantly reduced 5-ASA absorption in colonic cell lines. Moreover, OATP2B1 expression was dramatically downregulated in colon tissues from UC patients and dextran sodium sulfate (DSS)-induced colitis mice, and was also negatively correlated with colonic inflammation. Mechanistically, mixed proinflammatory cytokines downregulated the expression of OATP2B1 in a time- and concentration-dependent manner through the hepatocyte nuclear factor 4 α (HNF4α) pathway. In conclusion, OATP2B1 was the pivotal transporter involved in colonic 5-ASA uptake, which indicated that inducing OATP2B1 expression may be a strategy to promote 5-ASA uptake and further improve the concentration and anti-inflammatory efficacy of 5-ASA in UC. Schematic representation of the mechanism underlying the lower colonic 5-ASA concentrations in UC. UC-related proinflammatory cytokines downregulated OATP2B1 expression via the HNF4α-dependent pathway and subsequently decreased 5-ASA uptake, which led to a reduction in the colonic 5-ASA concentration in UC patients. [Display omitted] • Colonic 5-ASA concentration was reduced in DSS-induced colitis mice. • OATP2B1 was the crucial transporter involved in colonic 5-ASA uptake. • OATP2B1 expression was downregulated in colon tissues from UC patients and DSS-induced colitis mice. • Mixed proinflammatory cytokines downregulated the expression of OATP2B1 via the HNF4α-dependent pathway. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00092797
- Volume :
- 398
- Database :
- Academic Search Index
- Journal :
- Chemico-Biological Interactions
- Publication Type :
- Academic Journal
- Accession number :
- 178209803
- Full Text :
- https://doi.org/10.1016/j.cbi.2024.111074