Approximately 17% of our genome consists of copies of the retrotransposon "long interspersed element-1" (LINE-1 or L1). Patients with systemic lupus erythematosus (SLE) frequently have autoantibodies against the L1-encoded ORF1 protein (ORF1p), which correlate with disease activity and interferon gene signature. ORF1p is present in neutrophils from patients with active disease in perinuclear ribonucleoprotein particles that also contain Ro60 and nucleic acid sensors. Here, we report that treatment of neutrophils or monocytes with the demethylating agent 5-aza-deoxycytidine, interferon-α, tumor necrosis factor-α, and other cytokines or toll-like receptor agonists, induce a rapid increase in L1 transcripts. This increase was greater in cells from patients with SLE or rheumatoid arthritis (RA) than in cells from healthy donors, except that cells from SLE did not respond to interferon-α, presumably because most SLE patients have elevated type I interferons in vivo. Interferon-α also induced ORF1p in RA neutrophils with a subcellular distribution like that of ORF1p in freshly isolated SLE neutrophils. A luciferase reporter gene driven by the 5' untranslated region of L1, which controls its transcription, was also stimulated by interferon-α. These new insights into L1 transcriptional regulation indicate that it may play a more active role in antiviral immune responses.