Interleukin‐21 enhances Toll‐like receptor 2/4‐mediated cytokine production via phosphorylation in the STAT3, Akt and p38 MAPK signalling pathways in human monocytic THP‐1 cells

• Published in: Scandinavian journal of immunology Vol. 89; no. 6; pp. e12761 - n/a
• Main Authors: Jian, Leilei, Sun, Lin, Li, Changhong, Yu, Ruohan, Ma, Zhenzhen, Wang, Xinyu, Zhao, Jinxia, Liu, Xiangyuan
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.06.2019
• Subjects: 1-Phosphatidylinositol 3-kinase; Akt; AKT protein; cytokine production; Cytokines; Flow cytometry; Inflammation; Interferon; interleukin‐21; Janus kinase; Kinases; Ligands; Lipopolysaccharides; Lymphocytes; Lymphocytes T; MAP kinase; Monocytes; p38 MAPK; Peptidoglycans; Phosphorylation; Signal transduction; STAT3; Stat3 protein; TLR2 protein; TLR4 protein; Toll-like receptors; Toll‐like receptor 2/4; Transcription; Tumor necrosis factor; cytokine production; Akt; Toll-like receptor 2/4; interleukin-21; p38 MAPK; STAT3
• ISSN: 0300-9475; 1365-3083
• DOI: 10.1111/sji.12761

Interleukin‐21 (IL‐21) is a type I cytokine produced by activated T cells that promotes cytokine production in monocytes. Monocytes are activated by Toll‐like receptors (TLRs) to produce pro‐inflammatory mediators. However, little is known about the regulatory effect of IL‐21 on TLR‐mediated inflammation in human monocytes. This study investigated the potential association between IL‐21 and TLR2/4‐mediated inflammation in human monocytic THP‐1 cells. First, the expression of the IL‐21 receptor (IL‐21R) in human monocytic THP‐1 cells was examined by flow cytometry. Then, THP‐1 cells were treated with either the TLR2 ligand peptidoglycan (PGN) or the TLR4 ligand lipopolysaccharide (LPS) with or without IL‐21. Then, the production of several cytokines (IL‐6, IL‐8, TNF‐α, IFN‐γ and IL‐10), expression of TLR2/4, and activation of the downstream signaling pathways of mitogen‐activated protein kinase (MAPK), Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt), and nuclear factor‐kappa B (NF‐κB) were determined. We found that IL‐21R was highly expressed in human monocytic THP‐1 cells and that IL‐21 induced TLR2 and TLR4 expression and further enhanced PGN/LPS‐mediated TLR2/4 expression. In addition, IL‐21 also upregulated the expression of IL‐6, IL‐8, TNF‐α, IFN‐γ and IL‐10 and enhanced TLR2/4‐mediated cytokine production in THP‐1 cells via phosphorylation of the STAT3, Akt and p38 MAPK signalling pathways. Our study suggests, for the first time that IL‐21 enhances TLR2/4‐mediated cytokine production in human monocytic THP‐1 cells by activating the STAT3, PI3K/Akt and p38 MAPK signalling pathways.