Posttranscriptional gene regulation of IL-17 by the RNA-binding protein HuR is required for initiation of experimental autoimmune encephalomyelitis.

Abstract

IL-17 is a proinflammatory cytokine produced by activated Th17 cells and other immune cells. IL-17-producing Th17 cells are major contributors to chronic inflammatory and autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Although the transcriptional regulation of Th17 cells is well understood, the posttranscriptional regulation of IL-17 gene expression remains unknown. The RNA-binding protein HuR positively regulates the stability of many target mRNAs via binding the AU-rich elements present in the 3' untranslated region of many inflammatory cytokines including IL-4, IL-13, and TNF-α. However, the regulation of IL-17 expression by HuR has not been established. CD4(+) Th17 cells from HuR knockout mice had decreased IL-17 steady-state mRNA and protein levels compared with wild-type Th17 cells, as well as decreases in frequency of IL-17(+) cells. Moreover, we demonstrated that HuR directly binds to the IL-17 mRNA 3' untranslated region by using RNA immunoprecipitation and biotin pulldown assays. In addition, the knockout of HuR decreased cellular proliferation of CD4(+) T cells. Mice with adoptively transferred HuR KO Th17 cells had delayed initiation and reduced disease severity in the onset of experimental autoimmune encephalomyelitis compared with wild-type Th17 cells. Our results reveal a HuR-induced posttranscriptional regulatory mechanism of Th17 differentiation that influences IL-17 expression. These findings may provide novel therapeutic targets for the treatment of Th17-mediated autoimmune neuroinflammation.

• Authors: Jing Chen, Jason Cascio, Joseph D Magee, Patsharaporn Techasintana, Matthew M Gubin, Garrett M Dahm, Robert Calaluce, Shiguang Yu, Ulus Atasoy
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 191 Issue 11 Pg. 5441-50 (Dec 01 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 24166976 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ELAV Proteins
• Interleukin-17
• RNA, Messenger

Topics

• Adoptive Transfer
• Animals
• Cell Growth Processes (genetics)
• Cells, Cultured
• ELAV Proteins (genetics, immunology, metabolism)
• Encephalomyelitis, Autoimmune, Experimental (immunology)
• Female
• Gene Expression Regulation
• Interleukin-17 (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA Interference
• RNA, Messenger (metabolism)
• Th17 Cells (immunology)