https://phaidra.vetmeduni.ac.at/o:3681 Augmentative effects of leukemia inhibitory factor reveal a critical role for TYK2 signaling in vascular calcification Alesutan, Ioana Ioana Alesutan Johannes Kepler University of Linz Voelkl, Jakob Jakob Voelkl Johannes Kepler University of Linz / Charité - Universitätsmedizin Berlin / German Centre for Cardiovascular Research Eckardt, Kai-Uwe Kai-Uwe Eckardt Charité - Universitätsmedizin Berlin Vlahou, Antonia Antonia Vlahou Innsbruck Medical University Müller, Mathias Mathias Müller 0000-0002-7879-3552 University of Veterinary Medicine Vienna Bielesz, Bernhard Bernhard Bielesz Medical University of Vienna Antlanger, Marlies Marlies Antlanger Kepler Universitätsklinikum / Johannes Kepler University of Linz Suessner, Susanne Susanne Suessner Red Cross Transfusion Service of Upper Austria Cejka, Daniel Daniel Cejka Ordensklinikum Linz Barmherzige Schwestern Pasch, Andreas Andreas Pasch Johannes Kepler University of Linz Gollmann-Tepeköylü, Can Can Gollmann-Tepeköylü Innsbruck Medical University Makridakis, Manousos Manousos Makridakis Biomedical Research Foundation of the Academy of Athens Deisl, Christine Christine Deisl Johannes Kepler University of Linz Schuchardt, Mirjam Mirjam Schuchardt Charité - Universitätsmedizin Berlin / MSB Medical School Berlin Zickler, Daniel Daniel Zickler Charité - Universitätsmedizin Berlin Mitter, Gregor Gregor Mitter Johannes Kepler University of Linz Henze, Laura A. Laura A. Henze Johannes Kepler University of Linz Pitigala, Lakmi Lakmi Pitigala Johannes Kepler University of Linz Estepa, Misael Misael Estepa Charité - Universitätsmedizin Berlin Razazian, Mehdi Mehdi Razazian Johannes Kepler University of Linz Luong, Trang T. D. Trang T. D. Luong Johannes Kepler University of Linz Elsevier text eng Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD. Chronic Kidney Disease; Leukemia Inhibitory Factor; STAT3; TYK2; Vascular Calcification; Vascular Smooth Muscle Cells http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:3681/download 10.1016/j.kint.2024.07.011 application/pdf Kidney International 106(4), 611-624 (2024) Kidney International 106 4 611 624 3.45 MB 2024