Leukotriene B4 receptor 2 regulates the proliferation, migration, and barrier integrity of bronchial epithelial cells

Abstract

The airway epithelium plays a crucial role in the pathogenesis of asthma. The functions of leukotriene B4 receptor 2 (BLT2) on the airway epithelial cells remains unknown. In our study, BLT2 expression in 16HBE bronchial epithelial cells were manipulated by transfection with BLT2 overexpression plasmid or BLT2 small interference RNA. 16HBE cells were then exposed to BLT2 antagonist (LY255283) or BLT2 agonist (12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid [12-HHT] or CAY10583). The results showed that BLT2 overexpression, 12-HHT stimulation, or CAY10583 treatment resulted in the enhanced proliferation and migration of 16HBE cells. In addition, BLT2 showed an inhibitory effect on epithelial permeability as illustrated by the measurement of transepithelial electrical resistance (TER) and epithelial permeability, and a promoting effect on the levels of tight junction proteins (occludin and claudin-4) and phosphorylated p38 as demonstrated by real-time PCR and Western blotting analyses. These results suggest BLT2 as a key determinant of airway epithelial barrier integrity. On the contrary, RNAi-mediated knockdown or LY255283 treatment had reversed effects on the proliferation, migration, and epithelial barrier integrity. Together, our findings suggest the critical roles of BLT2 on the functions of bronchial epithelial cells and that BLT2 agonists are potential therapeutic agents for asthma treatment.

CYP2S1 is a synthetic lethal target in BRAFV600E-driven thyroid cancers

“…Current knowledge of CYP2S1 in endogenous function is largely related to eicosanoids metabolism, and some of its metabolic products have been identified, including 12-HHT, 5-oxo-eicosatetraenoic acid (5-oxoETE), 12-oxoETE, 15-oxoETE, etc. 12 Some of them have been demonstrated to be involved in tumor progression, such as 12-HHT and 5-oxoETE, 33,34 as supported by our data that CYP2S1 knockdown in BCPAP and 8505C cells dramatically reduced 12-HHT levels, and the restoration of 12-HHT could partially reverse inhibitory effect of CYP2S1 knockdown in cell viability. Besides, our data demonstrated that BRAF V600E promotes CYP2S1 transcription by activating MAPK/ERK cascade.…”

Tight junctions in the development of asthma, chronic rhinosinusitis, atopic dermatitis, eosinophilic esophagitis, and inflammatory bowel diseases

“…Restoration of bronchial epithelial barrier is crucial to the management of asthma 61 . The functions of leukotriene B4 receptor 2 on the airway epithelial cells have been recently discovered, and leukotriene B4 receptor 2 antagonists inhibit epithelial permeability, while promoting TJ protein levels of both occludin and claudin‐4 62 . Recent discoveries have revealed the protective effect of airway microbiome, such as that of CpG‐DNA against allergic airway inflammation 63 .…”

The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders

“…Although one 5-LO inhibitor, zileuton, is approved for treatment of asthma [51], interference with other molecules in LT biosynthesis and signaling pathway means that it is not fully effective. Roles for BLT2 in asthma have been reported, although to a lesser extent than that of BLT1 [49,52,53,54].…”

“…A recent in vivo study in BLT2-deficient mice indicates that BLT2 protects against allergic airway inflammation and that reduced expression of BLT2 by CD4 + T cells might contribute to the pathophysiology of asthma [52]. Also, an increasing number of studies have demonstrated that BLT2 has a protective role in allergic airway inflammation [49,53,54].…”