Background and purpose:The inflammatory cytokine interleukin-1 (IL-1) has profound actions in the brain, causing neuronal cell death and exacerbating brain damage. While circulating levels are normally low, IL-1 can be produced on the vascular side of the brain endothelium, and within the brain. The naturally occurring IL-1 receptor antagonist has been administered peripherally in a Phase II trial in acute stroke patients; understanding how IL-1 and IL-1 receptor antagonist penetrate the brain is, therefore, of considerable importance. Experimental approach: An in vitro blood-brain barrier model was generated by co-culture of porcine brain microvascular endothelial cells with astrocytes. The mechanisms of transcellular transport of IL-1b and IL-1 receptor antagonist were characterized in this model, using endocytosis inhibitors and IL-1 receptor-blocking antibodies. Key results: Transcellular IL-1b and IL-1 receptor antagonist transport was temperature-dependent and IL-1b was transported with higher affinity than IL-1 receptor antagonist. IL-1b inhibited IL-1 receptor antagonist transport more potently than IL-1 receptor antagonist inhibited IL-1b transport. Transport of IL-1b and IL-1 receptor antagonist was not via adsorptive-mediated endocytosis, although inhibition of microtubule assembly significantly attenuated transport of both cytokines. An antibody directed to the type II IL-1 receptor significantly reduced IL-1b transport. Conclusions and implications:These results are consistent with IL-1 and IL-1 receptor antagonist being transported across cultured cerebromicrovascular endothelial cells and suggest that IL-1b transport may occur via a type II IL-1 receptordependent mechanism. Understanding IL-1 transport into the brain may have benefits, particularly in enhancing penetration of IL-1 receptor antagonist into the brain.

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.

Interleukin (IL)-1 is an important neuroimmunomodulator and a key mediator of inflammation during brain disorders. It acts on neuronal and glial cells via binding to the IL-1 type 1 receptor and IL-1 receptor accessory protein (IL-1RAcP). More recently, a neuronal-specific isoform of IL-1RAcP, named IL-1RAcPb, has been identified. Our aim was to determine the role of IL-1RAcPb in IL-1 actions in neuronal and glial cells, and to further explore the signaling mechanisms of IL-1 in neurons. We found that IL-1RAcPb deletion had no effect on IL-1α- and IL-1β-induced activation of the extracellular signal-regulated kinase 1/2 or IL-6 release in glial cultures, although IL-6 release in response to high IL-1α concentration (30 IU/ml) was significantly reduced. We identified the p38 kinase as a key signaling element in IL-1α- and IL-1β-induced IL-6 synthesis and release in neuronal cultures. IL-1RAcPb deletion had no effect on IL-1α- and IL-1β-induced IL-6 release in neurons, but significantly reduced IL-1α- but not IL-1β-induced p38 phosphorylation. Our data demonstrate that the p38 signaling pathway plays an important role in IL-1 actions in neurons, and that IL-1RAcP may regulate some, but not all, neuronal activities in response to IL-1α.

Chronic subcutaneous infusion (from osmotic minipumps) of IL-1 beta (1 microgram/d) in male rats over seven days caused transient (1-3 d) increases in body temperature and reductions in body weight gain and food intake. By day 3, when colonic temperature was similar for vehicle and IL-1 infused groups, the acute responses (increases in temperature and VO2) to a maximal dose (1 microgram, sc) of IL-1 beta was almost identical in all animals. In a separate study intraperitoneal infusion of the same dose of IL-1 beta (1 microgram/d) increased the duration of changes in body temperature, weight and food intake, compared to subcutaneous infusion. In further groups of rats, pyrogenic responses to daily injections of IL-1 beta (1 microgram ip) were sustained for the entire 7 d period, but this treatment did not affect body weight. These data demonstrate that tolerance to infusion of IL-1 is not accompanied by reduced maximal responses to acute administration of IL-1, and indicate that more sustained effects of IL-1 are achieved by intraperitoneal rather than subcutaneous infusions, or by repetitive daily injections of the cytokine. These observations indicate that low levels of IL-1 release, maintained over periods of several days could be responsible for changes in body temperature and energy balance during chronic infections or inflammation.

Galanin‐like peptide (GALP) is thought to play a role in energy balance within the central nervous system. Experimental evidence shows that GALP has dichotomous actions on energy homeostasis; producing orexigenic effects in the short‐term, but anorexigenic effects over the longer‐term. These anorexic actions of GALP are very similar to that seen after peripheral or central injection of the cytokine interleukin‐1 (IL‐1). Thus the aim of this study was to test the hypothesis that IL‐1 mediates the effects of GALP on energy balance. Intracerebroventricular (icv) injection of GALP (1.6 nmol) in male Sprague‐Dawley rats stimulated food intake over 1 h, but decreased feeding, body weight at 24 h and cause a rise in core body temperature over 8 h (indirect evidence of an increase in energy expenditure). These longer‐term actions were inhibited by co‐infusion of the IL‐1 receptor antagonist, IL‐1ra. However, IL‐1ra had no effect on GALP‐induced acute stimulation of feeding. GALP injection (icv) also stimulated production of IL‐1 protein in selected brain areas, such as the periventricular brain region and these IL‐1 expressing cells were microglia. These data suggest GALP induces expression of IL‐1 in the brain and the anorexic and febrile actions of GALP are mediated by this cytokine.