Digoxin Attenuates Murine Experimental Colitis by Downregulating Th17-related Cytokines

Tani, Shinya; Takano, Ryosuke; Tamura, Satoshi; Oishi, Shinji; Iwaizumi, Moriya; Hamaya, Yasushi; Takagaki, Kosuke; Nagata, Toshi; Seto, Shintaro; Horii, Toshinobu; Kosugi, Isao; Iwashita, Toshihide; Osawa, Satoshi; Furuta, Takahisa; Miyajima, Hiroaki; Sugimoto, Ken

doi:10.1097/mib.0000000000001096

Cited by 12 publications

(6 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, they demonstrated that digoxin inhibits Th17 cell differentiation in the mouse experimental autoimmune encephalomyelitis model without influencing other T cell populations. Similar to the results of previous studies, digoxin efficiently attenuated the colitis induced by adoptive transfer of CD45RB+ CD4 T cells by downregulating Th17 cytokines and receptors, such as IL-17A, IFN- γ , and IL-23R, but did not influence mucosal TNF- α expression [102]. It will be important to investigate if digoxin holds therapeutic value for CD patients who are unresponsive to anti-TNF- α therapy.…”

Section: Nrs and Ibdsupporting

confidence: 78%

Nuclear Receptors in the Pathogenesis and Management of Inflammatory Bowel Disease

Ning

Lou

Zhang

et al. 2019

Mediators of Inflammation

View full text Add to dashboard Cite

Nuclear receptors (NRs) are ligand-dependent transcription factors that regulate the transcription of target genes. Previous epidemiological and genetic studies have documented the association of NRs with the risk of inflammatory bowel disease (IBD). Although the mechanisms of action of NRs in IBD have not been fully established, accumulating evidence has demonstrated that NRs play complicated roles in regulating intestinal immunity, mucosal barriers, and intestinal flora. As one of the first-line medications for the treatment of IBD, 5-aminosalicylic acid (5-ASA) activates peroxisome proliferator-activated receptor gamma (PPARγ) to attenuate colitis. The protective roles of rifaximin and rifampicin partly depend on promoting pregnane X receptor (PXR) expression. The aims of this review are to discuss the roles of several important NRs, such as PPARγ, PXR, vitamin D receptor (VDR), farnesoid X receptor (FXR), and RAR-related orphan receptor gammat (RORγt), in the pathogenesis of IBD and management strategies based on targeting these receptors.

show abstract

Section: Nrs and Ibdsupporting

confidence: 78%

Nuclear Receptors in the Pathogenesis and Management of Inflammatory Bowel Disease

Ning

Lou

Zhang

et al. 2019

Mediators of Inflammation

View full text Add to dashboard Cite

show abstract

“…In general, IL-17 and Th17 are the basis for the very large clinical potential of digoxin. Due to RORγt inhibition and subsequent suppression of Th17 cells, digoxin could be beneficial also for the treatment of rheumatoid arthritis, atherosclerosis, or colitis [ 72 , 73 , 74 ].…”

Section: Immunomodulatory Action Of Cgs In Treatment Of Autoimmune and Inflammatory Diseasesmentioning

confidence: 99%

Cardiac Glycosides as Immune System Modulators

2021

View full text Add to dashboard Cite

Cardiac glycosides (CGs) are natural steroid compounds occurring both in plants and animals. They are known for long as cardiotonic agents commonly used for various cardiac diseases due to inhibition of Na+/K+-ATPase (NKA) pumping activity and modulating heart muscle contractility. However, recent studies show that the portfolio of diseases potentially treatable with CGs is much broader. Currently, CGs are mostly studied as anticancer agents. Their antiproliferative properties are based on the induction of multiple signaling pathways in an NKA signalosome complex. In addition, they are strongly connected to immunogenic cell death, a complex mechanism of induction of anticancer immune response. Moreover, CGs exert various immunomodulatory effects, the foremost of which are connected with suppressing the activity of T-helper cells or modulating transcription of many immune response genes by inhibiting nuclear factor kappa B. The resulting modulations of cytokine and chemokine levels and changes in immune cell ratios could be potentially useful in treating sundry autoimmune and inflammatory diseases. This review aims to summarize current knowledge in the field of immunomodulatory properties of CGs and emphasize the large area of potential clinical use of these compounds.

show abstract

“…One of the first identified molecules affecting the function of RORγT was digoxin (Huh et al, 2011), which is a derivative of plants in the genus Digitalis that belongs to a group of compounds known as cardenolides. In a mouse model, it has been shown that treatment with high doses of digoxin has positive effects against experimental colitis (Xiao et al, 2014; Tani et al, 2017) and atherosclerosis (Shi et al, 2016) and attenuates acute cardiac allograft rejection (Wu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Digoxin, an Overlooked Agonist of RORγ/RORγT

et al. 2019

View full text Add to dashboard Cite

Digoxin was one of the first identified RORγT receptor inverse agonists inhibiting the differentiation of Th17 cells. However, this compound exhibits inhibitory activity at relatively high concentrations that mediate cytotoxic effects. We previously identified several cardenolides that are structurally similar to digoxin that were able to induce RORγ/RORγT-dependent transcription. These observations encouraged us to reanalyze the effects of digoxin on RORγ/RORγT-dependent transcription at low, noncytotoxic concentrations. Digoxin induced RORγ/RORγT-dependent transcription in HepG2 and Th17 cells. Furthermore, analysis of the transcriptomes of Th17 cells cultured in the presence of digoxin revealed the induction of the expression of numerous Th17-specific genes, including IL17A/F, IL21, IL22, IL23R, CCR4, and CCR6. Thus, our study, which includes data obtained from intact cells, indicates that digoxin, similar to other cardenolides, is a potent RORγ/RORγT receptor activator and that its structure may serve as a starting point for the design of dedicated molecules that can be used in the development of adoptive cell therapy (ACT).

show abstract

Digoxin Attenuates Murine Experimental Colitis by Downregulating Th17-related Cytokines

Cited by 12 publications

References 36 publications

Nuclear Receptors in the Pathogenesis and Management of Inflammatory Bowel Disease

Nuclear Receptors in the Pathogenesis and Management of Inflammatory Bowel Disease

Cardiac Glycosides as Immune System Modulators

Digoxin, an Overlooked Agonist of RORγ/RORγT

Contact Info

Product

Resources

About