Widespread inosine-containing mRNA in lymphocytes regulated by ADAR1 in response to inflammation.
Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional modification of pre-mRNA catalysed by an RNA-specific adenosine deaminase (ADAR). A-to-I RNA editing has been previously reported in the pre-mRNAs of brain glutamate and serotonin receptors and in lung tissue during inflammation. Here we report that systemic inflammation markedly induces inosine-containing mRNA to approximately 5% of adenosine in total mRNA. Induction was the result of up-regulation of A-to-I RNA editing as both dsRNA editing activity and ADAR1 expression were increased in the spleen, thymus and peripheral lymphocytes from endotoxin-treated mice. Up-regulation of ADAR1 was confirmed in vitro in T lymphocytes and macrophages stimulated with a variety of inflammatory mediators including tumour necrosis factor-alpha and interferon-gamma. A late induction of RNA editing was detected in concanavalin A-activated splenocytes stimulated with interleukin-2 in vitro. Taken together, these data suggest that a large number of inosine-containing mRNAs are produced during acute inflammation via up-regulation of ADAR1-mediated RNA editing. These events may affect the inflammatory and immune response through modulation of protein production.
Yang
Jing-Hua
JH
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA. jinghua.yang@yale.edu
Luo
Xiaoxing
X
Nie
Yongzhan
Y
Su
Yingjun
Y
Zhao
Qingchuan
Q
Kabir
Koroush
K
Zhang
Dexin
D
Rabinovici
Reuven
R
D000208:Acute Disease; D000243:Adenosine Deaminase / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D004731:Endotoxins; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D007288:Inosine / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017393:RNA Editing; D012330:RNA, Double-Stranded / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D015854:Up-Regulation
D004731:Endotoxins; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D007288:Inosine; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase