Interleukin‐3 stabilizes CD124/IL‐4α surface expression in mast cells via Tyk2 and STAT6

• Published in: Immunology 2023-05, Vol.169 (1), p.102-112
• Main Authors: Drube, Sebastian, Strotmann, Birgit, Wegner, Philine, Jäger, Ute‐Maria, Küchler, Claudia, Andreas, Nico
• Format: Article
• Language: English
• Subjects: Chains; Hsp90 protein; IL‐3; IL‐4Rα; Interleukin 6; Interleukin-13 Receptor alpha1 Subunit - metabolism; Interleukin-3; Interleukin-4 Receptor alpha Subunit - metabolism; Janus kinase; Janus kinase 2; Mast cells; Mast Cells - metabolism; Receptors, Interleukin-13 - metabolism; Receptors, Interleukin-4; regulation; Signal Transduction; Stat6 protein; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Tyk2; TYK2 Kinase - metabolism; Tyk2 protein
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13614

Interleukin (IL)‐4 signals can modulate mast cells, which express the IL‐4Rα chain. The IL‐4Rα can heterodimerise with the common γ‐chain and utilizes JAK1 and JAK2 for signal transduction, while complexes of IL‐4Rα with IL‐13Rα1 subunit mediates signals via JAK2 and Tyk2. Here, we report that IL‐3 is an essential factor for the continuous expression of the IL‐4Rα chain on mast cells, which did not express the IL‐13Rα1 chain. We demonstrate that the signals induced by IL‐3 important for IL‐4Rα expression are mediated by Tyk2 and STAT6 activation and the subsequent maintenance of HSP90 levels. In line with that, inhibition of either Tyk2, STAT6 or HSP90 impaired the IL‐3‐induced IL‐4Rα upregulation. Consequently, the IL‐3 maintained IL‐4Rα surface expression via Tyk2 is essential for the costimulatory effect of IL‐4 on the IL‐33‐induced production of IL‐6 and IL‐13. We show that interleukin (IL)‐3 is an essential factor for the continuous surface expression of the IL‐4Rα chain on mast cells. These signals induced by IL‐3 are mediated by Tyk2 and STAT6 activation and the subsequent maintenance of HSP90 levels. Thereby, stimulation with IL‐4 can induce a costimulatory effect on the IL‐33‐induced production of IL‐6 and IL‐13.