Interleukin‐29 Accelerates Vascular Calcification via JAK2/STAT3/BMP2 Signaling

Abstract

Background Vascular calcification (VC), associated with enhanced cardiovascular morbidity and mortality, is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells. Inflammation promotes VC initiation and progression. Interleukin (IL)‐29, a newly discovered member of type III interferon, has recently been implicated in the pathogenesis of autoimmune diseases. Here we evaluated the role of IL‐29 in the VC process and underlying inflammatory mechanisms. Methods and Results The mRNA expression of IL‐29 was significantly increased and positively associated with an increase in BMP2 (bone morphogenetic protein 2) mRNA level in calcified carotid arteries from patients with coronary artery disease or chronic kidney disease. IL‐29 and BMP2 proteins are colocalized in human calcified arteries. IL‐29 binding to its specific receptor IL‐28Rα (IL‐28 receptor α) (IL‐29/IL‐28Rα) inhibited the proliferation of rat vascular smooth muscle cells without altering cell apoptosis or migration. IL‐29 promoted the calcification of rat vascular smooth muscle cells and their osteogenic transdifferentiation in vitro as well as the rat aortic ring calcification ex vivo, induced by the calcification medium or osteogenic medium. The procalcification effect of IL‐29 was reduced by pharmacological inhibition of IL‐29/IL‐28Rα binding as well as suppression of janus kinase 2/signal transducer and activator of transcription pathway activation, accompanied by decreased BMP2 expression in the cultured rat vascular smooth muscle cells. Conclusions These results suggest an important role of IL‐29 in VC development, at least partly, via activating the janus kinase 2/signal transducer and activator of transcription 3 signaling. Inhibition of IL‐29 or its specific receptor, IL‐28Rα, may provide a novel strategy to reduce VC in patients with vascular diseases.

A Potential New Link Between Inflammation and Vascular Calcification

“… 7 , 10 Interestingly, interleukin‐29 has been shown to play a role in pro‐ as well as anti‐cancer effects by regulating proliferation and apoptosis. 10 A prior study, showing activation of signal transducer and activator of transcription‐3 during the spontaneous osteoblastic differentiation of vascular smooth muscle cells and induction by interleukins, such as interleukin‐6, 11 is consistent with the findings of Hao et al, 6 who further delineate the downstream regulation of interleukin‐29 on acceleration of vascular smooth muscle cell calcification via induction of osteogenic markers, bone morphogenetic protein‐2 (BMP‐2) and Runt‐related transcription factor 2, and downregulating smooth muscle markers alpha‐smooth muscle actin and smooth muscle protein 22α.…”

“…In this study by Hao et al, 6 and several others, rodents treated short term with high doses of vitamin D have been used as a model to study the mechanisms of VC. This model has been questioned on the basis that hypervitaminosis D may induce calcification through an entirely different mechanism, and over a longer time scale than operates in human calcific disease.…”

“…In this issue of the Journal of the American Heart Association ( JAHA ), Hao et al 6 provide evidence that expression of interleukin‐29 is upregulated in calcified carotid arteries from patients with coronary artery disease and chronic kidney disease. The authors also show that expression of interleukin‐28a, the human interleukin‐29 paralogue in mice, and its receptor interleukin‐28Ra are increased in the calcified aortic tissues of the vitamin D 3 –induced mouse model of VC.…”

“…Notably, all type III interferons, including interleukin‐29 and interleukin‐28a, bind to the same heterodimeric complex that comprises interleukin‐28Ra and interleukin‐10R2 subunits. 7 Using vascular smooth muscle cells and ex vivo rat aortic ring cultures in high phosphate or osteogenic media, Hao et al 6 demonstrate that interleukin‐29, which is known to activate the Janus kinase–signal transducer and activator of transcription signaling pathway, 8 promotes osteogenic differentiation and calcification. Conversely, Hao et al 6 showed that small‐molecule inhibitors antagonizing interleukin‐29 and its downstream Janus kinase–signal transducer and activator of transcription‐3 signaling pathway attenuate these processes.…”

“… 7 Using vascular smooth muscle cells and ex vivo rat aortic ring cultures in high phosphate or osteogenic media, Hao et al 6 demonstrate that interleukin‐29, which is known to activate the Janus kinase–signal transducer and activator of transcription signaling pathway, 8 promotes osteogenic differentiation and calcification. Conversely, Hao et al 6 showed that small‐molecule inhibitors antagonizing interleukin‐29 and its downstream Janus kinase–signal transducer and activator of transcription‐3 signaling pathway attenuate these processes. Although presumably from the inflammatory cells, it would be of great interest to identify the source of interleukin‐29.…”