Biologic basis for interleukin-1 in disease

Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

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The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression

▪ Abstract The interleukin-1 receptor antagonist (IL-1Ra) is a member of the IL-1 family that binds to IL-1 receptors but does not induce any intracellular response. Two structural variants of IL-1Ra have previously been described: a 17-kDa form that is secreted from monocytes, macrophages, neutrophils, and other cells (sIL-1Ra) and an 18-kDa form that remains in the cytoplasm of keratinocytes and other epithelial cells, monocytes, and fibroblasts (icIL-1Ra). An additional 16-kDa intracellular isoform of IL-1Ra has recently been described in neutrophils, monocytes, and hepatic cells. Both of the major isoforms of IL-1Ra are transcribed from the same gene through the use of alternative first exons. The two promoters regulating transcription of the secreted and intracellular forms have been cloned, and some of the functional cis-acting DNA regions have been characterized. The production of IL-1Ra is stimulated by many substances including adherent IgG, other cytokines, and bacterial or viral components. The...

INTERLEUKIN-1 RECEPTOR ANTAGONIST: Role in Biology

Recent studies indicate that IL-1alpha functions intracellularly in pathways independent of its cell surface receptors by translocating to the nucleus and regulating transcription. Similarly, the chromatin-associated protein HMGB1 acts as both a nuclear factor and a secreted proinflammatory cytokine. Here, we show that IL-33, an IL-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines, is an endothelium-derived, chromatin-associated nuclear factor with transcriptional repressor properties. We found that IL-33 is identical to NF-HEV, a nuclear factor preferentially expressed in high endothelial venules (HEV), that we previously characterized. Accordingly, in situ hybridization demonstrated that endothelial cells constitute a major source of IL-33 mRNA in chronically inflamed tissues from patients with rheumatoid arthritis and Crohn's disease. Immunostaining with three distinct antisera, directed against the N-terminal part and IL-1-like C-terminal domain, revealed that IL-33 is a heterochromatin-associated nuclear factor in HEV endothelial cells in vivo. Association of IL-33 with heterochromatin was also observed in human and mouse cells under living conditions. In addition, colocalization of IL-33 with mitotic chromatin was noted. Nuclear localization, heterochromatin-association, and targeting to mitotic chromosomes were all found to be mediated by an evolutionarily conserved homeodomain-like helix-turn-helix motif within the IL-33 N-terminal part. Finally, IL-33 was found to possess transcriptional repressor properties, associated with the homeodomain-like helix-turn-helix motif. Together, these data suggest that, similarly to IL1alpha and HMGB1, IL-33 is a dual function protein that may function as both a proinflammatory cytokine and an intracellular nuclear factor with transcriptional regulatory properties.

https://www.pnas.org/content/pnas/104/1/282.full.pdf

IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo

Ten years ago the cloning of two interleukin-1 molecules (IL-1 alpha and IL-1 beta) resolved the question of whether a single polypeptide could evoke a wide variety of biological effects During the past decade, the biology of IL-1 has greatly expanded our understanding of how the host responds to external challenges, such as injury and infection, as well as its role in several diseases We learned of the remarkable potency of IL-1 in the femtomolar range and of its ability to induce a response by triggering only one or two receptors per cell Unexpectedly, the IL-1 family of genes, receptors and associated molecules have been linked to those of Drosophila, nematodes, and microorganisms and IL-1 signal transduction is similar to that observed after cellular stress The cloning of IL-1 opened other avenues of fundamental biological interest For example, in addition to the two agonist molecules IL-1 alpha and IL-1 beta, a third member of the IL-1 gene family is a specific, high affinity receptor antagonist

The interleukin-1 family: 10 years of discovery.

The proliferative potential of human diploid endothelial cells is finite, and cellular senescence in vitro is accompanied by the failure of the endothelial cell to respond to exogenous growth factors. Senescent human endothelial cells were shown to contain high amounts of the transcript for the cytokine interleukin-1 alpha (IL-1 alpha), a potent inhibitor of endothelial cell proliferation in vitro. In contrast, transformed human endothelial cells did not contain detectable IL-1 alpha messenger RNA. Treatment of human endothelial cell populations with an antisense oligodeoxynucleotide to the human IL-1 alpha transcript prevented cell senescence and extended the proliferative life-span of the cells in vitro. Removal of the IL-1 alpha antisense oligomer resulted in the generation of the senescent phenotype and loss of proliferative potential. These data suggest that human endothelial cell senescence in vitro is a dynamic process regulated by the potential intracellular activity of IL-1 alpha.

http://science.sciencemag.org/content/sci/249/4976/1570.full.pdf

Pamela Voulalas

Papers

Extension of the life-span of human endothelial cells by an interleukin-1 alpha antisense oligomer