title: The Interleukin-1α Precursor is Biologically Active and is Likely a Key Alarmin in the IL-1 Family of Cytokines.
abstract: Among the 11 members of the IL-1 family cytokines, the precursors of IL-1α, IL-1β, and IL-33 have relatively long N-terminal pro-sequences of approximately 100 amino acid residues prior to the N-terminus of the mature forms. Compared to the mature forms secreted from the cell, 80-90% of the primary translation product is in the intracellular compartment in the precursor form. However, the precursors are readily released from cells during infections but also with non-infectious conditions such a hypoxia and trauma. In this setting, the precursors act rapidly as "alarmins" in the absence of a processing mechanism to remove the pro-sequence and generate a mature form. In the case of IL-1α, the release of the precursor activates adjacent cells via receptor-mediated signaling. However, there are no data comparing the specific activity of the IL-1α precursor to the mature form. In the present study, we compared the precursor and mature forms of recombinant human IL-1α, IL-1β, and IL-33 proteins on the induction of cytokines from A549 cells as well as from human peripheral blood mononuclear cells (PBMC). Similar to the mature form, the IL-1α precursor was active in inducing IL-6 and TNFα, whereas the precursor forms of IL-1β and IL-33 were not active. On PBMC, precursor and mature IL-1α at 0.04 and 0.2 nM were equally active in inducing IL-6. Given the fact that during necrotic cell death, the IL-1α precursor is released intact and triggers IL-1 receptors on tissue macrophages, these data identify the precursor form of IL-1α as a key player in sterile inflammation.
authors: Department of Medicine, University of Colorado Denver , Aurora, CO , USA.
authors: Busun
authors: B
authors: Kim
authors: Youngmin
authors: Y
authors: Lee
authors: Eunsom
authors: E
authors: Kim
authors: Areum
authors: A
authors: Kwak
authors: Soyoon
authors: S
authors: Ryoo
authors: Seung Hyeon
authors: SH
authors: Bae
authors: Tania
authors: T
authors: Azam
authors: Soohyun
authors: S
authors: Kim
authors: Charles A
authors: CA
authors: Dinarello
keywords: DAMPs; IL-1 family cytokine; precursor IL-1α; recombinant protein; sterile inflammation