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The Aurora kinase family is comprised of three serine/threonine kinases, Aurora-A, Aurora-B, and Aurora-C. Among these, Aurora-A and Aurora-B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases has been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis. Aurora kinases therefore represent promising targets for anticancer therapeutics. A number of Aurora kinase inhibitors (AKIs) have been generated; some of which are currently undergoing clinical evaluation. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in promoting tumorigenesis, the recent preclinical and clinical AKI data, and potential alternative routes for Aurora-A kinase inhibition.

Brain astrocytes play a pivotal role in the brain response to inflammation. They express IL-1 receptors including the type I IL-1 receptor (IL-1RI) that transduces IL-1 signals in cooperation with the IL-1 receptor accessory protein (IL-1RAcP) and the type II IL-1 receptor (IL-1RII) that functions as a decoy receptor. As glucocorticoid receptors are expressed on astrocytes, we hypothesized that glucocorticoids regulate IL-1 receptors expression. IL-1beta-activated mouse primary astrocytes were treated with 10(-6) M dexamethasone, and IL-1 receptors were studied at the mRNA and protein levels. Using RT-PCR, IL-1RI and IL-1RII but not IL-1RAcP mRNAs were found to be up-regulated by dexamethasone in a time-dependent manner. Dexamethasone (Dex), but not progesterone, had no effect on IL-1RI but strongly increased IL-1RII mRNA expression. Binding studies revealed an increase in the number of IL-1RII binding sites under the effect of Dex, but no change in affinity. These findings support the concept that glucocorticoids have important regulatory effect on the response of astrocytes to IL-1.

When activated by its ligand, the interleukin receptor type I (IL-1RI) transduces signals in cooperation with the IL-1 receptor accessory protein (IL-1RacP). In contrast, IL-1RII functions as a decoy receptor without participating in IL-1 signalling. Brain astrocytes are cellular targets of IL-1 and play a pivotal role in brain responses to inflammation. The regulation of IL-1 receptors on astrocytes by anti-inflammatory cytokines such as IL-4 and IL-10 has not been studied, despite its importance for understanding the way these cells respond to IL-1. Using RT-PCR, we first showed that the expression of IL-1RI and IL-1RII, but not IL-1RacP, mRNAs are up-regulated by IL-1 beta in a time-dependent manner. Using a radioligand binding technique, we then showed that astrocytes display an equivalent number of IL-1RI and IL-1RII. IL-1 beta decreases the number of IL-1RI binding sites, whereas it increases those of IL-1RII. IL-4 and IL-10 both up-regulate IL-1RII IL-1 beta-induced, but only IL-4 does so for IL-1RI. At the protein level, IL-4 and IL-10 dramatically reverse the ability of IL-1 beta to inhibit expression of IL-1RI but neither affects the ability of IL-1 beta to enhance the number of IL-1RII. Collectively, these results establish the existence of receptor cross-talk between pro- and anti-inflammatory cytokines on a critical type of cell that regulates inflammatory events in the brain.

Aging is associated with a decline in cognition in humans and rodents. Recently, these changes have been linked with decreased hippocampal neurogenesis. Physical exercise increases neurogenesis and reverses some of the cognitive deficits in elderly subjects, but the extent to which dietary supplementation may interact with physical exercise is unknown. Green tea contains high levels of epigallocatechin gallate (EGCG) that reduces age-related cognitive decline. Similarly, β-alanine (β-Ala) may be beneficial against cognitive aging. We tested the hypothesis that exercise (voluntary wheel running) and dietary supplementation with EGCG (1.5mg/g) and β-Ala (3.4 mg/g) would interact to improve cognition of aged mice. Balb/c mice (17 mo) served as sedentary controls or were provided access to running wheels for 4 weeks with or without EGCG + β-Ala. The Morris water maze (MWM) and contextual fear conditioning (CFC) were used to assess learning and memory. Hippocampal neurogenesis was assessed by labeling new neur...

The sections in this article are: 1 Proinflammatory Cytokines Regulate the Hypothalamic-Pituitary Adrenal Axis 2 Inflammatory Cytokines Regulate Secretion of Pituitary Growth Hormone 3 Cytokines and Their Receptors in the Central Nervous System 4 Cells in the Central Nervous System Synthesize Proinflammatory Cytokines 5 Receptors for Interleukin-1 in the Central Nervous System 6 Receptors for Tumor Necrosis Factor in the Central Nervous System 7 Receptors for Interleukin-6 in the Central Nervous System 8 Cytokines in the Central Nervous System Regulate Intermediary Metabolism 9 Synergistic Properties of Proinflammatory Cytokines 10 Growth Hormone and Prolactin: Pituitary Hormones Whose Receptors are Members of the Hematopoietin Receptor Superfamily 11 Growth Hormone and Insulin-Like Growth Factor-I 12 Insulin-Like Growth Factor-I Receptor: A Transmembrane Tyrosine Kinase 13 Immunological Actions of Growth Hormone and Insulin-Like Growth Factor-I: The Big Picture 14 Growth Hormone and Insulin-Like Growth Factor-I: Hematopoietic Cytokines? 14.1 Erythropoiesis 14.2 Lymphopoiesis 14.3 Myelopoiesis 15 Growth Hormone and Insulin-Like Growth Factor-I Demonstrate Classical Properties of Pleiotropic Lymphohemopoietic Cytokines 15.1 Promoting Cell Survival 15.2 Increasing DNA Synthesis 15.3 Enhancing Effector Functions 16 Hematopoietic Actions of Insulin-Like Growth Factor-I: Endocrine or Paracrine? 17 Clinical use of Recombinant Growth Hormone 18 Conclusion

The pro-inflammatory cytokine interleukin-1β (IL-1β) is strongly expressed during brain injury and is able to induce severe cellular brain damage via the production of soluble factors. Different processes regulate IL-1 biological activities, like the production of anti-inflammatory cytokines such as interleukin-4 (IL-4) and interleukin-10 (IL-10). In this report, we describe the sequential effects of IL-4 and IL-10 on the production of interleukin-6 (IL-6) induced by IL-1β in mouse primary astrocytes and compare these effects to those of the synthetic glucocorticoid agonist, dexamethasone. IL-6 secretion and IL-6 mRNA expression were determined by ELISA assay and a comparative RT-PCR method, respectively. Incubation of mouse astrocytes in primary culture simultaneously with IL-1β (10 ng/ml) + IL-10 (10 ng/ml) or IL-1β + dexamethasone (10−6 M) markedly reduced IL-1β induced IL-6 secretion and IL-6 mRNA expression, respectively, whereas simultaneous addition of IL-4 (10 ng/ml) did not alter the induction of IL-6 by IL-1β. In contrast, after 24 h of IL-1β treatment, the level of IL-6 was decreased below constitutive levels, and this change was reversed by addition of IL-4. IL-6 production in IL-1β pretreated cells was also increased by addition of IL-4, whereas IL-10 and dexamethasone had no effects. The delayed time dependent effect of IL-4 might be partially explained by the induction of IL-4 receptor α-chain mRNA expression by IL-1β. Therefore, we conclude that IL-10 and dexamethasone have rapid immunosuppressive effects on the astrocyte response to IL-1β stimulation, whereas IL-4, which has a delayed action, acts as an immune inducer. GLIA 26:12–21, 1999. © 1999 Wiley-Liss, Inc.

Peripheral and central injections of lipopolysaccharide (LPS), a cytokine inducer, and recombinant proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) induce sickness behavior in the form of reduced food intake and decreased social activities. Mechanisms of the behavioral effects of cytokines have been the subject of much investigation during the last 3 years. At the behavioral level, the profound depressing effects of cytokines on behavior are the expression of a highly organized motivational state. At the molecular level, sickness behavior is mediated by an inducible brain cytokine compartment that is activated by peripheral cytokines via neural afferent pathways. Centrally produced cytokines act on brain cytokine receptors that are similar to those characterized on peripheral immune and nonimmune cells, as demonstrated by pharmacologic experiments using cytokine receptor antagonists, neutralizing antibodies to specific subtypes of cytokine receptors, and gene targeting techniques. Evidence exists that different components of sickness behavior are mediated by different cytokines and that the relative importance of these cytokines is not the same in the peripheral and central cytokine compartments.

A decline in plasma concentrations of both growth hormone and IGF-I occurs during aging of humans and rodents, and this is accompanied by involution of the thymus gland. Exogenous growth hormone induces the synthesis of IGF-I, which acts on bone marrow-derived hematopoietic progenitors of the myeloid and lymphoid lineages to promote their replication and survival. The increase in survival of these cells is caused by the ability of IGF-I to inhibit their apopotic death. In contrast to the multipotential colony-stimulating-factor IL-3, inhibition of apoptosis by IGF-I requires the activation of the critical intracellular effector PI 3-kinase. These data establish that hematopoietic progenitors can use more than one intracellular signaling pathway in order to maintain their survival. The data also extend the original hypothesis 48 that IGF-I shares with the colony-stimulating factors the properties of promoting DNA synthesis and inhibiting programmed cell death. Collectively, these data establish that hematopoietic progenitor cells are important targets for IGF-I, and this is likely to be important in understanding thymic aging.

These data establish that cytokines, such as IL-1, can act on specific receptors within the brain to induce many symptoms of sickness. A number of inflammatory stimuli in the periphery can activate both the transcription and translation of IL-1 within the central nervous system. It will now be important to determine if similar central IL-1 pathways are activated during SLE and whether these central inflammatory cytokines are involved in the neurologic complications that often accompany this disease.

Rapidly proliferating transformed mammalian cells can be photodestroyed in vitro upon inducing the accumulation of endogenous protoporphyrin IX (Proto). Proto biosynthesis and accumulation were triggered by manipulation of the porphyrin-heme biosynthetic pathway. Proto accumulation in cultured cells was induced by treatment with 1.0 mM delta-aminolevulinic acid (ALA), a naturally occurring 5-carbon amino acid, for 3.5 h. In darkness, significant Proto accumulation became evident within 3.5 h of incubation. In the light, the accumulated tetrapyrroles triggered destruction of treated cells within the first 30 min of illumination, probably via the rapid oxidation of cellular constituents by singlet oxygen. Protoporphyrin IX accumulation and specific cell lysis increased significantly by inclusion of 0.75 mM 1,10-phenanthroline (Oph), a tetrapyrrole biosynthesis modulator. Slower growing untransformed cells did not accumulate significant amounts of Proto following ALA and Oph treatment unless stimulated to proliferate with the mitogenic lectin Concanavalin A.

Growth hormone was originally discovered because of its ability to promote linear growth in rodents and humans. It is now known that this molecule also augments a number of activities of leukocytes, such as antibody synthesis, cytolytic activity of T lymphocytes, natural killer cell activity, differentiation of neutrophils, production of tumor necrosis factor-alpha (TNF-alpha), and the synthesis of a thymic hormone known as thymulin. We have shown that growth hormone mimics one action of interferon-gamma (IFN-gamma) by augmenting the production of superoxide anion by macrophages and neutrophils. Growth hormone also is synthesized by leukocytes, which creates the possibility that it may act locally as a cytokine in lymphoid tissue. These findings show that a hormone that was originally isolated from the pituitary gland is involved in regulating host defense responses of leukocytes.

Growth hormone (GH) appears to play a major role in a reciprocal axis that has been postulated between the thymus and pituitary glands. Our previous studies showed that thymic structure, as well as T-cell proliferation and IL-2 synthesis, could be restored in aged female Wistar-Furth rats by the implantation of GH3 pituitary adenoma cells. These cells secrete GH and some prolactin. We have now used three different approaches to determine whether GH affects a variety of immune events in vivo in both old and young rodents, and whether GH3 cells can directly affect progenitor T-cells in nude rats that congenitally lack a thymus gland. To test the effects of GH in aged rats, 750 μg of pituitary-derived ovine GH was injected 2× daily into 26-month-old Fischer 344 rats for 5 weeks. This approach demonstrated that GH augments splenocyte proliferation to T-cell lectins as well as natural killer (NK) activity at low effector: target ratios even though morphologic characteristics of the thymus were not altered. To assess the effect of GH in young rodents, mice were studied that were transgenic for the rat metallothionein-GH gene. Histologic evaluation of thymus glands revealed that the amount of adipose tissue and the number of epithelial cells and Hassall's corpuscles are augmented in transgenic mice. Splenocyte proliferation at suboptimal mitogen doses is greater in transgenic than in control littermate mice, but neither IL-2 synthesis nor antibody synthesis to sheep erythrocytes is affected. The role of pituitary hormones on progenitor T-cells was then explored by implanting GH3 cells into Rowett nude rats. GH3 cells are unable to augment proliferation to T-cell lectins, IL-2 synthesis, antibody production to sheep erythrocytes, or NK activity in nude rats. Collectively, these experiments show that T-cells and NK cells from aged rats are not inherently defective because their proliferative responses to lectins and cytolytic activity can be augmented by exogenous GH. If GH affects progenitor T-cells, these effects are not apparent in nude rats. Finally, GH can also augment T-cell proliferative responses in young rodents, but the immunoenhancing effects are not as apparent as thos observed in immunocompromised aged animals.