In this study cell migration in response to

In this study, cell migration in response to LTD4 exhibited a typical bell-shaped dose-response curve with optimal activity at 10 nM. However, the effect of inhaled CysLTs on airway inflammatory cells in vivo has not been widely reported to date, therefore, the role of CysLTs in the development of allergen-induced airway eosinophilic inflammation remains poorly understood. Inhaled LTD4 has been shown to increase sputum eosinophils in subjects with Spectinomycin hydrochloride hydrate in two out of four studies [14, 15, 16, 17]. Inhaled LTE4 has been shown to elevate the number of eosinophils in sputum [17] and in bronchial biopsies [13]. Hemelaers and co-workers reported that CysLTs significantly enhanced the chemotactic activity of eosinophils in the sputum of asthmatics, whereas sputum eosinophil chemotactic activity was significantly inhibited by montelukast in vitro [18]. Their report has been an important observation that made locally released-CysLTs potential contributors to eosinophilic inflammation. To date, there have been only a few reports of the chemotaxis-inducing effects of CysLTs on human eosinophils in vitro. Nagy and co-workers reported that LTD4 did not elicit chemotaxis in eosinophils [5]. However, using an under-agarose technique, Spada and co-workers reported that LTD4 acts as a potent chemoattractant for human eosinophils from healthy donors, with a significant effect at 0.1 nM [6]. This chemotactic activity was completely abolished by the CysLT1 receptor antagonist SKF 104353 [6]. Spada et al. hypothesized that the absence of CysLT-induced chemotactic activity in vitro was due to the use of eosinophils from subjects with hypereosinophilia [6]. However, Fregonese and co-workers reported that LTC4, LTD4, and LTE4 may directly act as eosinophil chemoattractants in cells from atopic donors, and that eosinophil chemotaxis is completely abolished by the selective CysLT1 receptor antagonist montelukast [19]. From these contradictory reports, it is not clear whether CysLTs exert chemotactic effects on human eosinophils in vitro. Furthermore, there appear to be no other reports describing the chemotaxis-inducing effects of CysLTs on eosinophilic cell lines. Therefore, to our knowledge, the present findings in differentiated EoL-1 cells represent the first evidence for the induction of cell migration activity by CysLTs. Furthermore, the present in vitro model may be useful for clarifying the mechanisms underlying the induction of tissue eosinophilia by other lipid mediators. In conclusion, we demonstrated that LTD4 induces chemotaxis in EoL-1 cells via the activation of the CysLT1 receptor.This study provides novel insights into the role of CysLTs in airway eosinophilic inflammation. The present in vitro model may be useful for clarifying the mechanisms by which CysLTs induce tissue eosinophilia.
Declarations
Acknowledgement We would like to thank Editage (www.editage.jp) for English language editing.
Introduction Colorectal cancer (CRC) is associated with inflammation and high mortality worldwide [1,2]. Inflammatory bowel disease (IBD) results in chronic inflammation of the colon and a 30-fold increase in lifetime risk for colon cancer (CC) [3]. The inflammation-CC association is well-supported [[3], [4], [5]]. The role of pro-inflammatory eicosanoids, such as cysteinyl leukotrienes (CysLTs), in CC is well-documented [[6], [7], [8]]. CysLTs primarily act through two receptors, CysLT1 and CysLT2, mainly differing in their affinity for ligands [9,10]. CysLT1R has the highest affinity for LTD4, whereas CysLT2R is the high-affinity receptor for LTC4 [9,10]. We previously demonstrated that in CRC patients, increased CysLT1R expression offers a poor prognosis [6], whereas low CysLT1R expression coupled with high CysLT2R expression signifies a better prognosis [7]. LTD4-induced CysLT1R signaling triggers cell proliferation and migration [8], thereby promoting colon carcinogenesis, presumably via modifying β-catenin, COX-2, and BCL-2 expression [8].