Interleukin-1beta (IL-1β)-induced Notch ligand Jagged1 suppresses mitogenic action of IL-1β on human dystrophic myogenic cells.

Yuki Nagata,Yu-Ichi Goto,Madoka Ikemoto-Uezumi,Masafumi Matsuo,Naohiro Hashimoto,Tohru Kiyono,Kikuo Okamura,Atsushi Asakura

doi:10.1371/journal.pone.0188821

Abstract

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive muscle disorder caused by mutations in the dystrophin gene. Nonetheless, secondary processes involving perturbation of muscle regeneration probably exacerbate disease progression, resulting in the fatal loss of muscle in DMD patients. A dysfunction of undifferentiated myogenic cells is the most likely cause for the reduction of regenerative capacity of muscle. To clarify molecular mechanisms in perturbation of the regenerative capacity of DMD muscle, we have established several NCAM (CD56)-positive immortalized human dystrophic and non-dystrophic myogenic cell lines from DMD and healthy muscles. A pro-inflammatory cytokine, IL-1β, promoted cell cycle progression of non-dystrophic myogenic cells but not DMD myogenic cells. In contrast, IL-1β upregulated the Notch ligand Jagged1 gene in DMD myogenic cells but not in non-dystrophic myogenic cells. Knockdown of Jagged1 in DMD myogenic cells restored the IL-1β-promoted cell cycle progression. Conversely, enforced expression of Jagged1-blocked IL-1β promoted proliferation of non-dystrophic myogenic cells. In addition, IL-1β prevented myogenic differentiation of DMD myogenic cells depending on Jagged1 but not of non-dystrophic myogenic cells. These results demonstrate that Jagged1 induced by IL-1β in DMD myogenic cells modified the action of IL-1β and reduced the ability to proliferate and differentiate. IL-1β induced Jagged1 gene expression may be a feedback response to excess stimulation with this cytokine because high IL-1β (200–1000 pg/ml) induced Jagged1 gene expression even in non-dystrophic myogenic cells. DMD myogenic cells are likely to acquire the susceptibility of the Jagged1 gene to IL-1β under the microcircumstances in DMD muscles. The present results suggest that Jagged1 induced by IL-1β plays a crucial role in the loss of muscle regeneration capacity of DMD muscles. The IL-1β/Jagged1 pathway may be a new therapeutic target to ameliorate exacerbation of muscular dystrophy in a dystrophin-independent manner.

Highlights

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive muscle disorder affecting 1 in 3500 boys [1]
We found Notch ligand Jagged1 [36] gene expression was upregulated in the three dystrophic myogenic cell lines but not in the two non-dystrophic myogenic cell lines when cultured in a growth factor–enriched medium primary cultured myocyte growth medium (pmGM) (S3 Fig)
The present study showed that a proinflammatory cytokine, IL-1βinduced expression of a Notch ligand, Jagged1, resulted in suppression of cell cycle progression and myogenic differentiation in human dystrophic myogenic cells

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive muscle disorder affecting 1 in 3500 boys [1]. DMD is caused by mutations in the dystrophin gene that is expressed in terminally differentiated myofibers. The vast majority of DMD mutations result in the complete absence of dystrophin, which damages the myofiber membrane. The necrosis and degeneration of myofibers is followed by massive infiltration of immune cells, chronic inflammation, and vast muscle degeneration. Dystrophin deficiency is the proximate cause of DMD, secondary mechanisms involving persistent inflammation and impaired regeneration may exacerbate disease progression. Genome-wide gene expression profiling of skeletal muscle from DMD patients and mdx mice has revealed a molecular signature of dystrophinopathy, suggesting that secondary mechanisms, especially the inflammatory response, contribute to the pathogenesis [2,3,4]. The inflammatory response to myofiber damage is a candidate mechanism for exacerbation of the disease [5, 6]

Methods

Results

Conclusion