Expression of pleiotrophin, an important regulator of cell migration, is inhibited in intestinal epithelial cells by treatment with non-steroidal anti-inflammatory drugs.
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs for the suppression of inflammation and pain. However, the analgesic properties of NSAIDs are also associated with significant negative side effects, most notably in the gastrointestinal (GI) tract. Increasingly, evidence indicates that the ulcerogenic properties of some NSAIDs are not exclusively the result of inhibition of cyclooxygenase isoforms in the GI tract, and other mechanisms, including inhibition of cell migration and epithelial restitution, are being explored. Recently, microarray analysis was used to identify potential novel targets of NSAID activity in intestinal epithelial cells. Treated cells exhibited significant reductions in the gene expression of pleiotrophin (PTN), a cytokine and growth factor known to participate in angiogenesis and bone growth. This report aimed to confirm the microarray results reported previously, and to measure protein expression of PTN in intestinal epithelial cells. Furthermore, we also examined the effects of exogenous PTN on cell migration in the presence and absence of either NSAIDs with variable ulcerogenic potential or PTN-specific siRNA. Our results demonstrated that indomethacin and NS-398, two NSAIDs with ulcerogenic potential significantly decrease both gene and protein expressions of PTN in IEC-6 cells and protein expression in IEC-6-Cdx2 cells. Additionally, cell migration experiments with PTN siRNA showed that PTN is an important mediator of IEC-6 cell migration, and addition of exogenous PTN partially restores the deficits in cell migration caused by treatment with indomethacin and NS-398. Finally, measurement of PTN protein expression in the GI tract of horses treated with phenylbutazone showed that PTN expression is reduced by NSAIDs in vivo. Our results show that PTN is an important mediator of cell migration in IEC-6 cells, and PTN is a potential target through which NSAIDs may inhibit cell migration, epithelial restitution, and wound healing in the GI tract.
Publication Date: 2012-06-13 PubMed ID: 22691166DOI: 10.3109/08977194.2012.693920Google Scholar: Lookup
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- Journal Article
- Research Support
- N.I.H.
- Extramural
Summary
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This research article is about the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the expression of pleiotrophin (PTN), a cell migration regulator, in intestinal epithelial cells. The study finds that these drugs significantly decrease marked reductions in the gene and protein expression of PTN, affecting cell migration and potentially contributing to the negative side effects of NSAIDs in the gastrointestinal tract.
Overview and Background
- The focus of the research is on the effects of NSAIDs on pleiotrophin (PTN), a cytokine and growth factor, in intestinal epithelial cells.
- NSAIDs are common anti-inflammatory and pain-relieving drugs, with notable gastrointestinal side effects, which this research tries to investigate from a different perspective.
- The study follows up on previous microarray analyses, which hinted at the possible suppression of PTN by NSAIDs.
Methods and Approach
- The researchers aimed to validate the microarray results from previous studies and assess the protein expression of PTN in the observed cells.
- The effects of NSAIDs—particularly indomethacin and NS-398—on PTN expression were examined.
- The researchers also analysed the influence of externally added PTN on cell migration in the presence and absence of NSAIDs or PTN-specific siRNA.
- Animal trials were run using horses treated with phenylbutazone, a widely used NSAID, to investigate the implications on PTN protein expression in vivo.
Findings
- The NSAIDs indomethacin and NS-398 significantly lowered PTN gene and protein expressions in IEC-6 cells, and protein expression in IEC-6-Cdx2 cells.
- The experiments showed that PTN plays a crucial role in IEC-6 cell migration, and the addition of exogenous PTN partially recovers cell migration deficits caused by NSAIDs.
- PTN protein expression in the gastrointestinal tract of horses treated with phenylbutazone supported the in vitro findings, indicating a decrease of PTN expression due to NSAIDs in vivo.
Conclusion
- PTN is a significant facilitator for cell migration, and NSAIDs appear to inhibit PTN, potentially affecting cell migration and healing in the gastrointestinal tract.
- The research opens a potential new avenue for understanding the undesirable gastrointestinal side effects of NSAIDs, pointing to PTN as a possible target of NSAIDs’ activity.
Cite This Article
APA
Silver K, Desormaux A, Freeman LC, Lillich JD.
(2012).
Expression of pleiotrophin, an important regulator of cell migration, is inhibited in intestinal epithelial cells by treatment with non-steroidal anti-inflammatory drugs.
Growth Factors, 30(4), 258-266.
https://doi.org/10.3109/08977194.2012.693920 Publication
Researcher Affiliations
- USDA, Agricultural Research Service, Center for Grain and Animal Health Research, Manhattan, KS 66502, USA.
MeSH Terms
- Animals
- Anti-Inflammatory Agents, Non-Steroidal / pharmacology
- Bone and Bones / metabolism
- Carrier Proteins / biosynthesis
- Cell Line
- Cell Movement
- Cytokines / biosynthesis
- Epithelial Cells / metabolism
- Horses
- Indomethacin / pharmacology
- Intestinal Mucosa / metabolism
- Neovascularization, Pathologic
- Nitrobenzenes / pharmacology
- Oligonucleotide Array Sequence Analysis
- Phenylbutazone / pharmacology
- Sulfonamides / pharmacology
- Tissue Distribution
Grant Funding
- 1P20RR017686 / NCRR NIH HHS
Citations
This article has been cited 8 times.- Dubé PE, Liu CY, Girish N, Washington MK, Polk DB. Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice. Sci Rep 2018 Jun 14;8(1):9119.
- Pisanu A, Boi L, Mulas G, Spiga S, Fenu S, Carta AR. Neuroinflammation in L-DOPA-induced dyskinesia: beyond the immune function. J Neural Transm (Vienna) 2018 Aug;125(8):1287-1297.
- Shen D, Podolnikova NP, Yakubenko VP, Ardell CL, Balabiyev A, Ugarova TP, Wang X. Pleiotrophin, a multifunctional cytokine and growth factor, induces leukocyte responses through the integrin Mac-1. J Biol Chem 2017 Nov 17;292(46):18848-18861.
- Silver K, Littlejohn A, Thomas L, Bawa B, Lillich JD. Suppression of calpain expression by NSAIDs is associated with inhibition of cell migration in rat duodenum. Toxicology 2017 May 15;383:1-12.
- Fernández-Calle R, Vicente-Rodríguez M, Gramage E, Pita J, Pérez-García C, Ferrer-Alcón M, Uribarri M, Ramos MP, Herradón G. Pleiotrophin regulates microglia-mediated neuroinflammation. J Neuroinflammation 2017 Mar 4;14(1):46.
- Silver K, Littlejohn A, Thomas L, Marsh E, Lillich JD. Inhibition of Kv channel expression by NSAIDs depolarizes membrane potential and inhibits cell migration by disrupting calpain signaling. Biochem Pharmacol 2015 Dec 15;98(4):614-28.
- Hakkarainen TW, Steele SR, Bastaworous A, Dellinger EP, Farrokhi E, Farjah F, Florence M, Helton S, Horton M, Pietro M, Varghese TK, Flum DR. Nonsteroidal anti-inflammatory drugs and the risk for anastomotic failure: a report from Washington State's Surgical Care and Outcomes Assessment Program (SCOAP). JAMA Surg 2015 Mar 1;150(3):223-8.
- Henrotin Y, Pesesse L, Lambert C. Targeting the synovial angiogenesis as a novel treatment approach to osteoarthritis. Ther Adv Musculoskelet Dis 2014 Feb;6(1):20-34.
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