Abstract
Dysregulated inflammation contributes to disease pathogenesis in both the periphery and the brain. Cytokines are coordinators of inflammation and were originally defined as secreted mediators, released from expressing cells to activate plasma membrane receptors on responsive cells. However, a group of cytokines is now recognized as having dual functionality. In addition to their extracellular effects, these cytokines act inside the nuclei of cytokine-expressing or cytokine-responsive cells. Interleukin-1 (IL-1) family cytokines are key pro-inflammatory mediators, and blockade of the IL-1 system in inflammatory diseases is an attractive therapeutic goal. All current therapies target IL-1 extracellular actions. Here we review evidence that suggests IL-1 family members have dual functionality. Several IL-1 family members have been detected inside the nuclei of IL-1-expressing or IL-1-responsive cells, and intranuclear IL-1 is reported to regulate gene transcription and mRNA splicing. However, further work is required to determine the impact of IL-1 intranuclear actions on disease pathogenesis. The intranuclear actions of IL-1 family members represent a new and potentially important area of IL-1 biology and may have implications for the future development of anti-IL-1 therapies.
Highlights
The confusion surrounding the nature of the intranuclear effects of IL-1a is well demonstrated by the various reported roles of intranuclear IL-1a isoforms on cell proliferation
Endothelial cell ppIL-1a overexpression enhances endogenous IL-1a gene expression, indicating that an intracrine positive feedback loop may operate in these cells (Werman et al, 2004)
Pro- and ppIL-1a bind histone acetyl transferases (Buryskova et al, 2004), multifunctional enzymes that can regulate transcription by modifying chromatin structure and acetylating transcription factors such as NFkB (Chan and La Thangue, 2001; Chen et al, 2001). This interaction may explain how pro- and ppIL-1a can transactivate gene expression of a Gal-4 reporter when fused to the Gal-4 DNA-binding domain, and can directly activate NFkBand activator protein-1-dependent transcription (Buryskova et al, 2004; Werman et al, 2004). ppIL-1a interacts with necdin, HAX-1 (HS1-associated protein X-1, a ubiquitously expressed protein with poorly defined functions) and intranuclear IL-1RII (Yin et al, 2001; Hu et al, 2003; Kawaguchi et al, 2006). These interactions are implicated in the intranuclear effects of pro-IL-1a on cell proliferation and gene expression in systemic sclerosis (SSc) fibroblasts (Hu et al, 2003; Kawaguchi et al, 2006)
Summary
Inflammation is required for the efficient clearance of infections and repair of injured tissue, but dysregulated inflammation contributes to the pathogenesis of major peripheral and central nervous system (CNS) diseases. Interleukin-1 family members are commonly assumed to act primarily following release from IL-1 producing cells, via binding transmembrane IL-1 receptors on responsive cells. Mechanisms of IL-1a and b processing and release, and activation of the classical IL-1 signalling pathway on responsive cells, have been reviewed extensively elsewhere, (Nickel, 2003; Prudovsky et al, 2003; Mariathasan and Monack, 2007; Brikos and O’Neill, 2008) and are summarized here (see Figure 1). IL-1b induces changes in neuronal firing rates through neutral sphingomyelinase activation, and downstream Src kinase-mediated phosphorylation of the NMDA receptor subunit NR2B (Viviani et al, 2003) This rapid signalling pathway is implicated in the febrile response to IL-1b (Sanchez-Alavez et al, 2006).
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