Effect of TGF-β1 on eosinophils to induce cysteinyl leukotriene E4 production in aspirin-exacerbated respiratory disease.

Abstract

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-β1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-β1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-β1 and urinary LTE4. The function of TGF-β1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-β1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-β1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-β1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-β1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-β1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.

• Authors: Youngwoo Choi, Soyoon Sim, Dong-Hyun Lee, Hee-Ra Lee, Ga-Young Ban, Yoo Seob Shin, Yoon-Keun Kim, Hae-Sim Park
• Journal: PloS one (PLoS One) Vol. 16 Issue 8 Pg. e0256237 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 34437574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Leukotriene
• TGFB1 protein, human
• Transforming Growth Factor beta1
• leukotriene E4 receptor
• Leukotriene E4
• Glutathione Transferase
• p38 Mitogen-Activated Protein Kinases
• leukotriene-C4 synthase
• leukotriene D4 receptor
• Aspirin

Topics

• Adult
• Animals
• Aspirin (adverse effects, therapeutic use)
• Asthma, Aspirin-Induced (blood, genetics, pathology)
• Eosinophils (metabolism, pathology)
• Female
• Gene Expression Regulation (drug effects)
• Glutathione Transferase (urine)
• Humans
• Inflammation (blood, chemically induced, genetics, pathology)
• Leukotriene E4 (biosynthesis, blood, genetics)
• Male
• Mice
• Middle Aged
• Receptors, Leukotriene (metabolism)
• Respiratory System (drug effects, metabolism, pathology)
• Respiratory System Abnormalities (blood, chemically induced, genetics, pathology)
• Transforming Growth Factor beta1 (blood, genetics)
• p38 Mitogen-Activated Protein Kinases (genetics)