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Leukotriene B4 Receptor Type 2 Accelerates the Healing of Intestinal Lesions by Promoting Epithelial Cell Proliferation S

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Leukotriene B4 Receptor Type 2 Accelerates the Healing of Intestinal Lesions by Promoting Epithelial Cell Proliferation S Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2020/01/15/jpet.119.263145.DC1 1521-0103/373/1/1–9$35.00 https://doi.org/10.1124/jpet.119.263145 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 373:1–9, April 2020 Copyright ª 2020 by The American Society for Pharmacology and Experimental Therapeutics Leukotriene B4 Receptor Type 2 Accelerates the Healing of Intestinal Lesions by Promoting Epithelial Cell Proliferation s Yui Matsumoto, Yukiko Matsuya, Kano Nagai, Kikuko Amagase, Kazuko Saeki, Kenjiro Matsumoto, Takehiko Yokomizo, and Shinichi Kato Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan (Yui.M, Yuk.M., K.N., K.A., K.M., S.K.); Laboratory of Pharmacology and Pharmacotherapy, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (K.A.); and Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan (K.S., T.Y.) Received October 8, 2019; accepted January 2, 2020 Downloaded from ABSTRACT Leukotriene B4 receptor type 2 (BLT2) is a low-affinity leukotriene also negated by Go6983, a protein kinase C (PKC) inhibitor, U- B4 receptor that is highly expressed in intestinal epithelial cells. 73122, a phospholipase C (PLC) inhibitor, LY255283, a BLT2 Previous studies demonstrated the protective role of BLT2 in antagonist, and pertussis toxin that inhibits G protein–coupled jpet.aspetjournals.org experimentally induced colitis. However, its role in intestinal receptor signaling via Gi/o proteins. Thus, BLT2 plays an lesion repair is not fully understood. We investigated the role of important role in intestinal wound repair. Moreover, this effect BLT2 in the healing of indomethacin-induced intestinal lesions in is mediated by the promotion of epithelial cell proliferation via the mice. There was no significant different between wild-type (WT) Gi/o protein–dependent and PLC/PKC signaling pathways. The and BLT2-deficient (BLT2KO) mice in terms of the development BLT2 agonists are potential therapeutic agents for the treatment of indomethacin-induced intestinal lesions. However, healing of of intestinal lesions. these lesions was significantly impaired in BLT2KO mice compared with WT mice. In contrast, transgenic mice with SIGNIFICANCE STATEMENT at ASPET Journals on September 26, 2021 intestinal epithelium–specific BLT2 overexpression presented The healing of indomethacin-induced Crohn’s disease–like in- with superior ileal lesion healing relative to WT mice. An testinal lesions was impaired in mice deficient in low-affinity immunohistochemical study showed that the number of Ki- leukotriene B4 receptor type 2 (BLT2). They presented with 67–proliferative cells was markedly increased during the healing reduced epithelial cell proliferation during the healing. In con- of intestinal lesions in WT mice but significantly attenuated in trast, healing was promoted in mice overexpressing intestinal BLT2KO mice. Exposure of cultured mouse intestinal epithelial epithelial BLT2. In cultured intestinal epithelial cells, the BLT2 cells to CAY10583, a BLT2 agonist, promoted wound healing agonist CAY10583 substantially accelerated wound repair by and cell proliferation in a concentration-dependent manner. enhancing cell proliferation rather than migration. Thus, BLT2 Nevertheless, these responses were abolished under serum- plays an important role in the intestinal lesions via acceleration of free conditions. The CAY10583-induced proliferative effect was epithelial cell proliferation. Introduction acid (12-HHT) (Yokomizo et al., 2001; Okuno et al., 2008). The 12-HHT is a byproduct of thromboxane A2 via cyclooxygenase Leukotriene B4 receptor type 2 (BLT2) is a low-affinity (COX) followed by thromboxane synthase. It is an endogenous leukotriene B receptor activated by various eicosanoids, in- 4 BLT2 ligand (Okuno et al., 2008). BLT2 is highly expressed in cluding 12(S)-hydroxyeicosatetraenoic acid, 15(S)-hydroxyeicosa- the epithelia of the small intestine and colon and in skin tetraenoic acid, and 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic keratinocytes (Iizuka et al., 2005; Liu et al., 2014). BLT2- deficient (BLT2KO) mice presented with aggravation of dextran sulfate sodium–induced colitis via impairment of the epithelial This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sport, and Culture of Japan [Grant barrier (Iizuka et al., 2010). BLT2 overexpression in Madin- 19K07109 to K.M., Grant 18K06692 to K.A., Grant 18K6923 to K.S., Grant Derby canine kidney II epithelial cells exhibited increased 15H05904, and Grant 18H02627 to T.Y.] and the Takeda Science Foundation (to K.M.). transepithelial electrical resistance and decreased fluorescein Y.M., Y.M., and K.N. contributed equally to this work. isothiocyanate–dextran leakage via upregulation of the major The authors have no conflicts of interest to disclose. https://doi.org/10.1124/jpet.119.263145. tight junction component claudin 4 (Ishii et al., 2016). Thus, s This article has supplemental material available at jpet.aspetjournals.org. BLT2 helps maintain epithelial barrier function and integrity. ABBREVIATIONS: 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid; BLT2, leukotriene B4 receptor type 2; BLT2KO, BLT2 deficient; COX, cyclooxygenase; EGF, epidermal growth factor; IGF, insulin-like growth factor; IL, interleukin; MPO, meloperoxidase; NSAID, nonsteroidal anti-inflammatory drug; PKC, protein kinase C; PLC, phospholipase C; PTX, pertussis toxin; TBP, TATA-binding protein; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; villin-BLT2-Tg, transgenic with intestinal epithelium–specific overexpression of BLT2; WT, wild type; YAMC, young adult mouse colon. 1 2 Matsumoto et al. Earlier studies disclosed that skin wound healing was Indomethacin-Induced Intestinal Lesions. The mice were delayed in BLT2KO mice relative to wild-type (WT) mice. A fasted for 18 hours, allowed free access to food for 2 hours, and synthetic BLT2 agonist accelerated skin wound healing in administered subcutaneous indomethacin (Sigma-Aldrich Corp., St. both normal and diabetic db/db mice (Liu et al., 2014). An Louis, MO). Indomethacin was suspended in saline with a drop of in vitro scratch assay on primary keratinocytes and keratino- Tween 80 (Wako Pure Chemical Industries Ltd., Osaka, Japan). The dosages were at 8 mg/kg for BALB/c mice and 10 mg/kg for C57BL/6 cyte cell lines showed that BLT2 activation accelerated re- mice. Normal mice received vehicle only (Tween 80/saline). To epithelialization by promoting cell migration (Liu et al., 2014). highlight hemorrhagic intestinal lesions, each mouse was intrave- BLT2 overexpression and activation enhanced bronchial nously injected with 100 ml of 1% (w/v) Evans blue solution at epithelial cell proliferation and migration (Liu et al., 2018). 30 minutes before sacrifice (Kawahara et al., 2011). The mice were COX inhibition by nonsteroidal anti-inflammatory drugs sacrificed at 24, 48, 72, and 96 hours after indomethacin injection. (NSAIDs) such as aspirin and diclofenac inhibited 12-HHT Their small intestines were excised, fixed in 2% (v/v) formalin, synthesis and delayed skin and corneal wound healing (Liu opened longitudinally, and examined for lesions under a dissecting et al., 2014; Iwamoto et al., 2017). These findings suggest that microscope (S6D; Leica, Wetzlar, Germany) at Â10. The areas BLT2 plays important roles in skin and bronchium healing by (square millimeter) of the visible lesions were measured after promoting epithelial cell proliferation and migration. blinding the investigators to the group assignments. The intestinal tissues were fixed in 10% (v/v) neutralized formalin, embedded in The intestinal epithelium maintains mucosal homeostasis paraffin, sectioned at 4 mm thickness, and stained with H&E. and regulates inflammation and wound repair and healing. Histologic injury was observed under a microscope (BX51; Olympus, Downloaded from Disruption of these functions results in inflammatory bowel Tokyo, Japan) at Â100. disease and chronic mucosal inflammation. Efficient epithe- Determination of Myeloperoxidase Activity. Myeloperoxi- lial repair and healing are vital for the reversal of mucosal dase (MPO) activity was determined using a previously reported inflammation and the recovery of homeostasis (Leoni et al., method (Kato et al., 2012) with modifications. The animals were 2015a,b). Epithelial cell migration and proliferation are sacrificed 72 hours after indomethacin injection, and their small closely associated with physiologic remodeling and wound intestines were excised. The tissues were homogenized in 50 mM healing after tissue injury (Yamaoka et al., 2014; Seidelin phosphate buffer containing 0.5% (w/v) hexadecyltrimethylammo- jpet.aspetjournals.org et al., 2015). nium bromide (pH 6.0; Wako Pure Chemical Industries Ltd.). The homogenized samples were subjected thrice to freeze-thawing and NSAIDs are commonly prescribed for the treatment of centrifuged at 2000g and 4°C for 10 minutes. MPO activity was various inflammatory diseases. However, they may injure determined by adding 5 ml supernatant to 45 ml of 10 mM phosphate the stomach and small intestine (Bjarnason et al., 1993; buffer (pH 6.0) and 50 ml of 1.5 M o-dianisidine HCl (Sigma-Aldrich Yamada et al., 1993; Konaka et al., 1999). There are patho- Corp.) containing 0.0005% (v/v) hydrogen peroxide.
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