Anti-Inflammatory Activities of an Anti-Histamine Drug, Loratadine, by Suppressing TAK1 in AP-1 Pathway

• Published in: International journal of molecular sciences Vol. 23; no. 7; p. 3986
• Main Authors: Jang, Jiwon, Hunto, Stephanie Triseptya, Kim, Ji Won, Lee, Hwa Pyoung, Kim, Han Gyung, Cho, Jae Youl
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 03.04.2022; MDPI
• Subjects: Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - adverse effects; anti-inflammatory effect; Antihistamines; AP-1; Apoptosis; c-Fos protein; c-Jun protein; Cell cycle; Cytokines; Drug dosages; Fos protein; Gastritis; Gastritis - chemically induced; Gelatinase B; Gene expression; Histamine; Histamine Antagonists - therapeutic use; Inflammation; Kinases; Loratadine; Loratadine - pharmacology; Loratadine - therapeutic use; Macrophages; Mice; Phosphorylation; Proteins; RAW 264.7 Cells; Signal transduction; TAK1; TAK1 protein; Transcription activation; Transcription Factor AP-1 - metabolism; Transcription factors; Western blotting; anti-inflammatory effect; TAK1; AP-1; Loratadine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23073986

Loratadine is an anti-histamine routinely used for treating allergies. However, recent findings have shown that Loratadine may also have anti-inflammatory functions, while their exact mechanisms have not yet been fully uncovered. In this paper, we investigated whether Loratadine can be utilized as an anti-inflammatory drug through a series of in vitro and in vivo experiments using a murine macrophage cell line and an acute gastritis mouse model. Loratadine was found to dramatically reduce the expression of pro-inflammatory genes, including MMP1, MMP3, and MMP9, and inhibit AP-1 transcriptional activation, as demonstrated by the luciferase assay. Therefore, we decided to further explore its role in the AP-1 signaling pathway. The expression of c-Jun and c-Fos, AP-1 subunits, was repressed by Loratadine and, correspondingly, the expression of p-JNK, p-MKK7, and p-TAK1 was also inhibited. In addition, Loratadine was able to reduce gastric bleeding in acute gastritis-induced mice; Western blotting using the stomach samples showed reduced p-c-Fos protein levels. Loratadine was shown to effectively suppress inflammation by specifically targeting TAK1 and suppressing consequent AP-1 signaling pathway activation and inflammatory cytokine production.