U1 RNA induces innate immunity signaling

Robert W. Huffman, Tal Gazitt, Mark F. Foecking, Robert A. Ortmann, Michael Misfeldt, Rebecca Jorgenson, Steven L. Young, Eric L. Greidinger

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Objective. The U1-70-kd RNP is a prominent target of autoimmunity in connective tissue diseases. In this study, we explored whether its endogenous ligand, U1 RNA, mediates a proimmune signal and may be immunogenic. Methods. We assayed the proliferation of control and MyD88-knockout splenocytes in response to in vitro-synthesized U1 RNA, and measured interleukin-6 (IL-6) and IL-8 secretion induced by U1 RNA in a human cell line competent for signaling through Toll-like receptor 3 (TLR-3) and TLR-5. Results. Treatment with U1 RNA or with poly(I-C), a known agonist of TLR-3, induced approximately twice as much control splenocyte proliferation as did treatment with RNase-digested U1 RNA. Proliferation in response to either poly(I-C) or U1 RNA by MyD88-knockout splenocytes was similarly attenuated. Similar to polyd-C), U1 RNA induced significant secretion of both IL-6 and IL-8 from a TLR-3-expressing human cell line; in contrast, the TLR-5 agonist flagellin induced predominantly IL-8 secretion. Pretreatment of U1 RNA with RNase abolished IL-6 and IL-8 secretion. Conclusion. U1 RNA is capable of inducing manifestations consistent with TLR-3 activation. The ability of U1 RNA (which has a substantial double-stranded secondary structure) to activate TLR-3 may contribute to the immunogenicity of the U1-70-kd autoantigen. Stimulation of innate immunity by native MNA molecules with a double-stranded secondary structure may help explain the high prevalence of autoimmunity to RNA binding proteins.

Original languageEnglish (US)
Pages (from-to)2891-2896
Number of pages6
JournalArthritis and Rheumatism
Volume50
Issue number9
DOIs
StatePublished - Sep 1 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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    Huffman, R. W., Gazitt, T., Foecking, M. F., Ortmann, R. A., Misfeldt, M., Jorgenson, R., Young, S. L., & Greidinger, E. L. (2004). U1 RNA induces innate immunity signaling. Arthritis and Rheumatism, 50(9), 2891-2896. https://doi.org/10.1002/art.20428