Submitted to: Growth Factors
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/11/2012
Publication Date: 8/15/2012
Citation: Silver, K.S., Desormaux, A., Freeman, L.C., Lillich, J.D. 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. Interpretive Summary: Cell migration is an important component in wound repair in the digestive tract where abrasive ingested food can cause damage to the cells that line the digestive tract (epithelial cells). Upon wounding, epithelial cells of the digestive tract flatten, spread, and move into the damaged area, restoring the unbroken barrier. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs worldwide for the alleviation of pain and inflammation. NSAIDs are known to cause damage to the epithelia of the digestive tract in part through inhibiting cell migration, though the mechanisms behind these effects are largely unknown. Genomic approaches designed to identify novel targets of NSAID activity associated with cell migration have suggested that pleiotrophin (PTN), an important mediator of cell migration in bone and vascular tissues, is affected by NSAID treatment. Accordingly, we showed that PTN stimulates cell migration in cultured intestinal epithelial cells, and that NSAIDs inhibited both gene and protein expression of PTN in cell culture and in horses. Our results suggest that PTN is a clinically relevant target of NSAID activity, and disruption of PTN expression may be one mechanism through which NSAIDs inhibit wound healing and promote damage to the lining of the digestive tract. Understanding the mechanisms underlying the toxic effects of NSAIDs on the digestive tract is critical to the pharmaceutical industry in the design of new NSAIDs that lack toxic side effects. Furthermore, this information is important to physicians seeking to alleviate symptoms associated with chronic NSAID treatment in their patients.
Technical 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 (IEC-6). 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 expression 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.