Phospholipase C-γ as a Potential Therapeutic Target for Graves’ Orbitopathy

• Published in: Endocrinology and metabolism (Seoul) Vol. 38; no. 6; pp. 739 - 749
• Main Authors: Roh, Tae Hoon, Chae, Min Kyung, Ko, Jae Sang, Kikkawa, Don O., Jang, Sun Young, Yoon, Jin Sook
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Endocrine Society 01.12.2023; 대한내분비학회
• Subjects: graves ophthalmopathy; inflammation; orbital fibroblasts; Original; phospholipase c gamma; proinflammatory cytokines; u73122; 내과학; Orbital fibroblasts; Inflammation; U73122; Proinflammatory cytokines; Graves ophthalmopathy; Phospholipase C gamma
• ISSN: 2093-596X; 2093-5978; 2093-5978
• DOI: 10.3803/EnM.2023.1780

Background: Phospholipase C-γ (PLC-γ) plays a crucial role in immune responses and is related to the pathogenesis of various inflammatory disorders. In this study, we investigated the role of PLC-γ and the therapeutic effect of the PLC-specific inhibitor U73122 using orbital fibroblasts from patients with Graves’ orbitopathy (GO).Methods: The expression of phospholipase C gamma 1 (PLCG1) and phospholipase C gamma 2 (PLCG2) was evaluated using polymerase chain reaction in GO and normal orbital tissues/fibroblasts. The primary cultures of orbital fibroblasts were treated with non-toxic concentrations of U73122 with or without interleukin (IL)-1β to determine its therapeutic efficacy. The proinflammatory cytokine levels and activation of downstream signaling molecules were determined using Western blotting.Results: PLCG1 and PLCG2 mRNA expression was significantly higher in GO orbital tissues than in controls (P<0.05). PLCG1 and PLCG2 mRNA expression was significantly increased (P<0.05) in IL-1β, tumor necrosis factor-α, and a cluster of differentiation 40 ligand-stimulated GO fibroblasts. U73122 significantly inhibited the IL-1β-induced expression of proinflammatory molecules, including IL-6, IL-8, monocyte chemoattractant protein-1, cyclooxygenase-2, and intercellular adhesion molecule-1 (ICAM-1), and phosphorylated protein kinase B (p-Akt) and p38 (p-p38) kinase in GO fibroblasts, whereas it inhibited IL-6, IL-8, and ICAM-1, and p-Akt and c-Jun N-terminal kinase (p-JNK) in normal fibroblasts (P<0.05).Conclusion: PLC-γ-inhibiting U73122 suppressed the production of proinflammatory cytokines and the phosphorylation of Akt and p38 kinase in GO fibroblasts. This study indicates the implications of PLC-γ in GO pathogenesis and its potential as a therapeutic target for GO.