The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

Ariel Werman, Rachel Werman-Venkert, Rosalyn White, Jae Kwon Lee, Batsheva Werman, Yakov Krelin, Elena Voronov, Charles A. Dinarello, Ron N. Apte

Research output: Contribution to journalArticlepeer-review

285 Scopus citations

Abstract

Although most cytokines are studied for biological effects after engagement of their specific cell surface membrane receptors, increasing evidence suggests that some function in the nucleus. In the present study, the precursor form of IL-1α was overexpressed in various cells and assessed for activity in the presence of saturating concentrations of IL-1 receptor antagonist to prevent receptor signaling. Initially diffusely present in the cytoplasm of resting cells, IL-1α translocated to the to nucleus after activation by endotoxin, a Toll-like receptor ligand. The IL-1α precursor, but not the C-terminal mature form, activated the transcriptional machinery in the GAL4 system by 90-fold; a 50-fold increase was observed using only the IL-1α propiece, suggesting that transcriptional activation was localized to the N terminus where the nuclear localization sequence resides. Under conditions of IL-1 receptor blockade, intracellular overexpression of the precursor and propiece forms of IL-1α were sufficient to activate NF-κB and AP-1. Stable transfectants overproducing precursor IL-1α released the cytokines IL-8 and IL-6 but also exhibited a significantly lower threshold of activation to subpicomolar concentrations of tumor necrosis factor α or IFN-γ. Thus, intracellular functions of IL-1α might play an unforeseen role in the genesis of inflammation. During disease-driven events, the cytosolic precursor moves to the nucleus, where it augments transcription of proinflammatory genes. Because this mechanism of action is not affected by extra-cellular inhibitors, reducing intracellular functions of IL-1α might prove beneficial in some inflammatory conditions.

Original languageEnglish
Pages (from-to)2434-2439
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number8
DOIs
StatePublished - 22 Feb 2004

ASJC Scopus subject areas

  • General

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