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.

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.

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 poly(I‐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.

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 RNA molecules with a double‐stranded secondary structure may help explain the high prevalence of autoimmunity to RNA binding proteins.