The interleukin-1 alpha precursor is biologically active and is likely a key alarmin in the IL-1 family of cytokines

Among the 11 members of the ILI family cytokines, the precursors of IL-1 alpha, IL-1 beta, 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-1 alpha, the release of the precursor activates adjacent cells via receptor-mediated signaling. However, there are no data comparing the specific activity of the Ma precursor to the mature form. In the present study, we compared the precursor and mature forms of recombinant human IL-1 alpha, IL-1 beta, 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-1 alpha precursor was active in inducing IL-6 and INF alpha, whereas the precursor forms of IL-1 beta and IL-33 were not active. On PBMC, precursor and mature IL-1 alpha at 0.04 and 0.2 nM were equally active in inducing IL-6. Given the fact that during necrotic cell death, the IL-1 alpha precursor is released intact and triggers 1151 receptors on tissue macrophages, these data identify the precursor form of IL-1 alpha as a key player in sterile inflammation.