Regulation of the eicosanoid pathway by tumour necrosis factor alpha and leukotriene D4 in intestinal epithelial cells

Yudina, Yulyana; Parhamifar, Ladan; Bengtsson, Anders; Juhas, Maria; Sjölander, Anita

doi:10.1016/j.plefa.2008.09.024

Cited by 20 publications

(18 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[43] have shown that ATRA can down-regulate the colon inflammatory response as measured by tumor necrosis factor alpha (TNFα) levels, in patients with IBD in vitro and in a murine colitis model in vivo . We previously found that TNFα also down-regulates CysLT 2 R while up-regulating CysLT 1 R in colon cancer cells [44], an observation that also highlights the importance of maintaining receptor balance in epithelial cells [18]. …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The cysteinyl leukotriene 2 receptor contributes to all-transretinoic acid-induced differentiation of colon cancer cells

Bengtsson¹,

Jönsson

Magnusson

et al. 2013

BMC Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundCysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT1R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT2R) is lost. Further, our previous data indicate that patients with high CysLT1R and low CysLT2R expression have a poor prognosis. In this study, we examined whether the balance between CysLT1R and CysLT2R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA).MethodsTo determine the effect of ATRA on CysLT2R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions.ResultsATRA treatment induces CysLT2R mRNA and protein expression without affecting CysLT1R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor (RAR) dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C4 synthase, the enzyme responsible for the production of the ligand for CysLT2R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT2R-specific inhibitor.ConclusionsThis study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

“…LTD 4 is a ligand for CysLT 1 R that up-regulates both LTC 4 S and CysLT 2 R in intestinal epithelial and colon cancer cells [44]. These activities are associated with differentiation, but the underlying signaling mechanism remained unclear [29].…”

Section: Discussionmentioning

confidence: 99%

The cysteinyl leukotriene 2 receptor contributes to all-transretinoic acid-induced differentiation of colon cancer cells

Bengtsson¹,

Jönsson

Magnusson

et al. 2013

BMC Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, LTD 4 can up-regulate the mRNA expression of CysLT 2 R in monocytes [43] and epithelial cells [44] and the cytokines IL-4, IL-8 and IFN-γ [28], [45], [46] can up-regulate the mRNA expression of CysLT 2 R in several different cell types. Since a binding site for IRF-7 was present in the putative promoter region of the CysLT 2 R , we hypothesized that the IFN-α would be able to induce CysLT 2 R expression via transcription factor IRF-7.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cysteinyl Leukotriene Receptor 2 Expression—A Potential Anti-Tumor Mechanism

et al. 2011

Self Cite

View full text Add to dashboard Cite

BackgroundThe cysteinyl leukotrienes receptors (CysLTRs) are implicated in many different pathological conditions, such as inflammation and cancer. We have previously shown that colon cancer patients with high CysLT1R and low CysLT2R expression demonstrate poor prognosis. Therefore, we wanted to investigate ways for the transcriptional regulation of CysLT2R, which still remains to be poorly understood.Methodology/Principal FindingsWe investigated the potential role of the anti-tumorigenic interferon α (IFN-α) and the mitogenic epidermal growth factor (EGF) on CysLT2R regulation using non-transformed intestinal epithelial cell lines and colon cancer cells to elucidate the effects on the CysLT2R expression and regulation. This was done using Western blot, qPCR, luciferase reporter assay and a colon cancer patient array. We found a binding site for the transcription factor IRF-7 in the putative promoter region of CysLT2R. This site was involved in the IFN-α induced activity of the CysLT2R luciferase reporter assay. In addition, IFN-α induced the activity of the differentiation marker alkaline phosphatase along with the expression of mucin-2, which protects the epithelial layer from damage. Interestingly, EGF suppressed both the expression and promoter activity of the CysLT2R. E-boxes present in the CysLT2R putative promoter region were involved in the suppressing effect. CysLT2R signaling was able to suppress cell migration that was induced by EGF signaling.Conclusions/SignificanceThe patient array showed that aggressive tumors generally expressed less IFN-α receptor and more EGFR. Interestingly, there was a negative correlation between CysLT2R and EGFR expression. Our data strengthens the idea that there is a protective role against tumor progression for CysLT2R and that it highlights new possibilities to regulate the CysLT2R.

show abstract

“…Interestingly, quite different effects of LTC 4 and LTD 4 were published for intestinal epithelial cells and CaCo-2 cells; LTD 4 promoted proliferation, while this was not found for LTC 4 (61). This effect of LTD 4 involved increased expression of COX-2 and PGE 2 (62,63). Accordingly, in a mouse model of lung cancer, the production of CysLTs and PGE 2 increased considerably during tumor growth (24).…”

Section: Formation Of Cyslt In Coincubations Of Pbecs With Mm6 Cellsmentioning

confidence: 98%

Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4

Lukić

Jie

Idborg

et al. 2016

Journal of Lipid Research

View full text Add to dashboard Cite

Leukotrienes (LTs) are mediators of inflammation (1) formed by immune cells in response to pathogens or danger signals. When cells are stimulated, cytosolic phospholipase A 2  (cPLA 2 ) and 5-lipoxygenase (LO) migrate to the nuclear membrane, arachidonic acid (AA) is released from nuclear membrane phospholipids, and LTA 4 is produced (2). Efficient translocation and activation of 5-LO requires two scaffold proteins, 5-LO activating protein (FLAP) and coactosin-like protein (CLP) (3). LTA 4 is then further metabolized by cytosolic LTA 4 hydrolase to LTB 4 , or by LTC 4 synthase (LTC 4 S) to LTC 4 . LTC 4 S is primarily located at the nuclear membrane together with FLAP, and both proteins are members of the family of membrane bound proteins involved in eicosanoid and glutathione metabolism (MAPEG). LTC 4 and its metabolites, LTD 4 and LTE 4 , are jointly referred to as the cysteinyl LTs (CysLTs). CysLTs elicit edema formation, mucus secretion, and smooth muscle contraction, as well as eosinophil trafficking and tissue remodeling, and thus contribute to symptoms in several chronic inflammatory diseases, such as asthma (4). There are at least three different receptors for the CysLTs; in the lung, bronchoconstriction and other effects are mediated via CysLT1. LTD 4 has a 10-to 50-fold higher potency for activation of CysLT1 compared with LTC 4 , while LTE 4 is the least active (5, 6). Thus, metabolism of LTC 4 to LTD 4 may have a considerable impact on CysLT1-mediated effects, also depending on further conversion to LTE 4 . Abstract Leukotrienes (LTs

show abstract

Regulation of the eicosanoid pathway by tumour necrosis factor alpha and leukotriene D4 in intestinal epithelial cells

Cited by 20 publications

References 34 publications

The cysteinyl leukotriene 2 receptor contributes to all-transretinoic acid-induced differentiation of colon cancer cells

The cysteinyl leukotriene 2 receptor contributes to all-transretinoic acid-induced differentiation of colon cancer cells

Regulation of Cysteinyl Leukotriene Receptor 2 Expression—A Potential Anti-Tumor Mechanism

Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4

Contact Info

Product

Resources

About