ORIGINAL ARTICLE

Alternative splicing factor ASF/SF2 is down regulated in inflamed muscle

Z Xiong^1,2, A Shaibani^3,4, Y-P Li³, Y Yan², S Zhang^1,2, Y Yang², F Yang^1,2, H Wang^1,3,5, X-F Yang^1,2,3,6

¹ Laboratory of Immunopathology, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
² Laboratory of Immunopathology, Baylor College of Medicine, Houston, Texas, USA
³ Department of Medicine, Baylor College of Medicine
⁴ Nerve & Muscle Center of Texas, St Luke’s Episcopal Hospital, Houston
⁵ Biology of Inflammation Center, Section of Atherosclerosis and Lipoprotein Research, Baylor College of Medicine
⁶ Department of Immunology, Baylor College of Medicine

Correspondence to:
X-F Yang
Department of Pharmacology, Temple University School of Medicine, 3420 N Broad Street, MRB Room 300, Philadelphia, PA 19140, USA; franklinxf_yang{at}yahoo.com

Background: In our recent studies, alternative splicing has been shown to have a major role in inflammation and autoimmune muscle diseases.

Aim: To examine the novel hypothesis that the expression of an essential alternative splicing factor, alternative splicing factor 2 (ASF/SF2), is modulated in muscle inflammation.

Methods: ASF/SF2 expression in muscle biopsy samples from eight patients with inflammatory myopathy and six non-myositic controls was determined by using western blot with anti-ASF/SF2 antibodies. To further elucidate the mechanism of reduced ASF/SF2 expression in inflamed muscle, differentiated C2C12 myotubes were stimulated with proinflammatory cytokine tumour necrosis factor (TNF), followed by western blot analysis of ASF/SF2 expression.

Results: ASF/SF2 expression in the muscle biopsy samples from patients with inflammatory myopathy was found to be lower (mean of relative densitometric units 41.1 (2SD 20.7)) than that of the non-myositic controls (mean of relative densitometric units 76.7 (39.6); p<0.05). In addition to this, ASF/SF2 expression was seen to be significantly down regulated (sevenfold) in C2C12 myotubes compared with expression variations in the ß-actin control (0.62-fold; mean 1.22 (0.40); p<0.05).

Conclusion: Collectively, it is shown, for the first time, that alternative splicing factor ASF/SF2 is down regulated in autoimmune inflammatory myositis—potentially via a TNF-mediated pathway. The development of (1) novel autoantigen isoform microarrays for disease diagnosis and prognosis; (2) novel autoantigen-tolerising treatments for autoimmune diseases; and (3) novel splicing-redirection treatments can be facilitated by the ongoing study of alternative splicing of autoantigen transcripts.

Abbreviations: ASF/SF2, alternative splicing factor 2; mRNA, messenger RNA; PM, polymyositis; SR protein, serine/arginine-rich protein; TNF, tumour necrosis factor

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