PubMed Health⌕ Search

Biomedical subjects

Keith W Kelley

Publications and source records attributed to Keith W Kelley.

At least 19 recordsLinked to original sources
PubMed2007

Protein hormones and immunity.

A number of observations and discoveries over the past 20 years support the concept of important physiological interactions between the endocrine and immune systems. The best known pathway for transmission of information from the immune system to the neuroendocrine system is humoral in the form of cytokines, although neural transmission via the afferent vagus is well documented also. In the other direction, efferent signals from the nervous system to the immune system are conveyed by both the neuroendocrine and autonomic nervous systems. Communication is possible because the nervous and immune systems share a common biochemical language involving shared ligands and receptors, including neurotransmitters, neuropeptides, growth factors, neuroendocrine hormones and cytokines. This means that the brain functions as an immune-regulating organ participating in immune responses. A great deal of evidence has accumulated and confirmed that hormones secreted by the neuroendocrine system play an important role in communication and regulation of the cells of the immune system. Among protein hormones, this has been most clearly documented for prolactin (PRL), growth hormone (GH), and insulin-like growth factor-1 (IGF-I), but significant influences on immunity by thyroid-stimulating hormone (TSH) have also been demonstrated. Here we review evidence obtained during the past 20 years to clearly demonstrate that neuroendocrine protein hormones influence immunity and that immune processes affect the neuroendocrine system. New findings highlight a previously undiscovered route of communication between the immune and endocrine systems that is now known to occur at the cellular level. This communication system is activated when inflammatory processes induced by proinflammatory cytokines antagonize the function of a variety of hormones, which then causes endocrine resistance in both the periphery and brain. Homeostasis during inflammation is achieved by a balance between cytokines and endocrine hormones.

Animals↗
PubMed2006

Twenty years of research on cytokine-induced sickness behavior.

Cytokine-induced sickness behavior was recognized within a few years of the cloning and expression of interferon-alpha, IL-1 and IL-2, which occurred around the time that the first issue of Brain, Behavior, and Immunity was published in 1987. Phase I clinical trials established that injection of recombinant cytokines into cancer patients led to a variety of psychological disturbances. It was subsequently shown that physiological concentrations of proinflammatory cytokines that occur after infection act in the brain to induce common symptoms of sickness, such as loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue. This syndrome was defined as sickness behavior and is now recognized to be part of a motivational system that reorganizes the organism's priorities to facilitate recovery from the infection. Cytokines convey to the brain that an infection has occurred in the periphery, and this action of cytokines can occur via the traditional endocrine route via the blood or by direct neural transmission via the afferent vagus nerve. The finding that sickness behavior occurs in all mammals and birds indicates that communication between the immune system and brain has been evolutionarily conserved and forms an important physiological adaptive response that favors survival of the organism during infections. The fact that cytokines act in the brain to induce physiological adaptations that promote survival has led to the hypothesis that inappropriate, prolonged activation of the innate immune system may be involved in a number of pathological disturbances in the brain, ranging from Alzheimer's disease to stroke. Conversely, the newly-defined role of cytokines in a wide variety of systemic co-morbid conditions, ranging from chronic heart failure to obesity, may begin to explain changes in the mental state of these subjects. Indeed, the newest findings of cytokine actions in the brain offer some of the first clues about the pathophysiology of certain mental health disorders, including depression. The time is ripe to begin to move these fundamental discoveries in mice to man and some of the pharmacological tools are already available to antagonize the detrimental actions of cytokines.

Adaptation, Physiological↗
PubMed2006

Insulin-like growth factor-I enhances the biological activity of brain-derived neurotrophic factor on cerebrocortical neurons.

Insulin-like growth factor (IGF)-I and brain-derived neurotrophic factor (BDNF) act within the brain to enhance neuronal survival and plasticity. We extend these findings by showing that the presence of both neurotrophins is required to depress the rise in intracellular Ca2+ caused by glutamate in primary cultures of cerebrocortical neurons. IGF-I enhanced expression of BDNF receptors (Trk-B) and increased the ability of BDNF to induce ERK1/2 phosphorylation. This IGF-I-induced increase in BDNF responsiveness describes a new interaction between these peptides in the brain.

Animals↗
PubMed2006

C-jun N-terminal kinase mediates tumor necrosis factor-alpha suppression of differentiation in myoblasts.

The stress kinase c-jun N-terminal kinase (JNK) was recently shown to be involved in the pathophysiology of major inflammatory conditions, including Alzheimer's disease, stroke, obesity, and type II diabetes. However, the role of JNK in regulating inflammatory events in skeletal muscle is only beginning to be explored. IGF-I is the major hormone that promotes muscle growth and development. Here we used a novel, JNK interacting protein (JIP)-derived JNK peptide inhibitor to establish that JNK suppresses the biological activity of IGF-I in skeletal muscle progenitor cells. In these myoblasts, TNFalpha and its downstream receptor substrates, neutral-sphingomyelinase (N-SMase) and N-acetyl-d-sphingosine (C2-ceramide), induce JNK kinase activity in a time-dependent manner. Consistent with these results, TNFalpha induces JNK binding to insulin receptor substrate 1 (IRS-1) but is unable to inhibit IGF-I-induced IRS-1 tyrosine phosphorylation in myoblasts that are treated with the JNK peptide inhibitor. More importantly, JNK activation induced by TNFalpha, C2-ceramide, and N-SMase is associated with reduced expression of the critical muscle transcription factor myogenin as well as the differentiation marker myosin heavy chain (MHC). The JNK peptide inhibitor, but not the control peptide, completely reverses this inhibition of both myogenin and MHC. In the absence of IGF-I, TNFalpha, C2-ceramide, N-SMase and the JNK inhibitor are inactive, as shown by their inability to affect IRS tyrosine phosphorylation and protein expression of myogenin and MHC. These results establish that the resistance of muscle progenitor cells to IGF-I, which is caused by inflammatory stimuli, is mediated by the JNK stress kinase pathway.

Animals↗
PubMed2006

Effects of insulin-like growth factor-I on cytokine-induced sickness behavior in mice.

Central administration of insulin-like growth factor-I (IGF-I) attenuates sickness behavior in response to the cytokine inducer lipopolysaccharide. The present study was designed to determine the respective roles of the two main proinflammatory cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta), in these effects. Male CD1 mice were injected into the lateral ventricle (i.c.v.) of the brain with optimal amounts of either TNFalpha (50 ng) or IL-1beta (2 ng) that induce sickness behavior. Behavioral responses to IGF-I (0, .1, and 1 microg) also given i.c.v. were measured at various time intervals before and after treatment with the two proinflammatory cytokines. Mice treated with TNFalpha and IL-1beta lost body weight and displayed equivalent reductions in social exploration and instances of immobility. At the dose of .1 microg, IGF-I attenuated these signs of sickness in TNFalpha-but not in IL-1beta-treated mice. At the dose of 1 microg, IGF-I attenuated IL-1beta-induced immobility and the reduction in social exploration but had no effect on loss of body weight. These findings indicate that IGF-I is more potent in attenuating sickness behavior induced by TNFalpha than that caused by IL-1beta, which is consistent with the relative specificity of the TNFalpha/IGF-I interactions in the brain.

Animals↗
PubMed2005

Pentoxifylline and insulin-like growth factor-I (IGF-I) abrogate kainic acid-induced cognitive impairment in mice.

Hippocampal insults involving neuroimmune mechanisms can impair learning and memory in a variety of tasks. The present study was designed to assess the effect of pentoxifylline, an inhibitor of tumor necrosis factor alpha (TNFalpha), and insulin-like growth factor-I (IGF-I) on kainate (KA)-induced impairment in spatial memory. Male mice received a subcutaneous injection of a dose of KA (15 mg/kg) that had no cytotoxic effect on hippocampal neurons as confirmed by Fluorojade B staining. This dose resulted in an impairment of spatial memory in a two-trial recognition task 11 days later. Intraperitoneal administration of pentoxifylline (200 mg/kg) abrogated this effect. Repeated intracerebroventricular injection of IGF-I (2 microg/mouse on day 1 followed by 1 microg/mouse on days 2-5) abrogated KA-induced deficits in spatial memory whereas acute IGF-I (2 microg/mouse on day 1 only) had mixed effects. These findings indicate that endogenous TNFalpha is probably involved in the detrimental effects of kainate on cognition and that exogenous IGF-I can oppose these effects, probably by antagonizing TNFalpha-induced neurotoxicity.

Analysis of Variance↗
PubMed2005

Bacille Calmette-Guérin inoculation induces chronic activation of peripheral and brain indoleamine 2,3-dioxygenase in mice.

BACKGROUND: Activation of the indoleamine 2,3-dioxygenase (IDO) enzyme and the resulting decrease in plasma tryptophan (TRP) levels appears to be a crucial link in the relationship between cytokines and depression. We aimed to develop an experimental model of chronic IDO activation based on bacille Calmette-Guérin (BCG) infection that elicits a robust increase in levels of interferon (IFN)- gamma, a key cytokine in the activation of IDO. METHODS: Mice were inoculated intraperitoneally with BCG (10(7) cfu/mouse). Lung and brain IDO activity was measured over time, together with plasma levels of TRP and IFN- gamma. RESULTS: BCG induced, over the course of several weeks, a chronic increase in serum IFN- gamma levels that was associated with a sustained enhancement of lung and brain IDO activity and with decreases in peripheral (serum and lungs) and brain concentrations of TRP, with different time courses between tissues. CONCLUSIONS: The model of BCG-induced IDO activation will be useful for the study of the consequences of peripheral immune activation in the brain and the role of TRP metabolism in cytokine-induced mood alteration.

Animals↗
PubMed2005

IL-1beta-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes.

Chronic inflammation appears to play a critical role in type 2 diabetes and its complications. Here we tested the hypothesis that this inflammatory dysregulation affects the IL-1beta system and has functional consequences in the brain. Diabetic, db/db, and nondiabetic, db/+, mice were administered i.p. LPS, a potent cytokine inducer, at a dose of 100 microg/kg/mouse. db/db mouse innate immune-associated sickness behavior was 14.8, 33, 44.7, and 34% greater than that of db/+ mice at 2, 4, 8, and 12 h, respectively. When a fixed dose of LPS was used (5 microg/mouse), db/db mouse sickness was again enhanced 18.4, 22.2, and 14.5% at 4, 8, and 12 h as compared with db/+ mice. In diabetic mice, peritoneal macrophages produced more IL-1beta in response to LPS, and peritoneal levels of IL-1beta induced by LPS were increased. Importantly, IL-1R antagonist and type 2 IL-1 receptor (IL-1R2) failed to up-regulate in response to LPS in db/db mice. Finally, both peripheral and central administration of IL-1beta, itself, induced sickness in db/db mice that mimicked the effects of peripheral LPS and was significantly greater than that seen in db/+ mice. Taken together, these results indicate that IL-1beta-mediated innate immunity is augmented in db/db mice both at the periphery and in the brain, and the mechanism is due to diabetes-associated loss of IL-1beta counterregulation.

Animals↗
PubMed2005

alpha-Tocopherol and selenium facilitate recovery from lipopolysaccharide-induced sickness in aged mice.

The elderly suffer a decline in immune function that increases their vulnerability to infections. Because antioxidants improve some age-related deficits in immune and cognitive function, our goal was to determine whether dietary alpha-tocopherol (alpha-T) and selenium inhibit LPS-induced sickness behavior in aged mice. Male BALB/c mice were fed modified AIN93-M diets that were low, adequate, or high in both alpha-T (10, 75, or 500 mg/kg) and selenium (0.05, 0.15, or 2 mg/kg) from 18 to 21 mo of age. Sickness was quantified by measuring time in social exploration of a novel juvenile conspecific. The lipopolysaccharide treatment reduced social exploration by 74% at 2 h, regardless of diet. By 4 h, aged mice fed the low diet were 88% less social, whereas mice fed the adequate and high diets displayed only approximately 40% reductions due to LPS treatment. Mice fed the low diet had greater LPS-induced weight loss than mice fed the high diet. Plasma alpha-T concentration and glutathione peroxidase (GPX) activity increased with each increment in alpha-T and selenium 24 h post-LPS treatment. Brain alpha-T concentration and GPX activity were lower in mice fed the low diet than in those fed the adequate or high diet. Regardless of diet, interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)alpha mRNA levels were elevated by LPS approximately 3-fold in cortex, cerebellum, striatum, and hippocampus. Thus, antioxidants inhibit sickness behavior independently of IL-6, IL-1beta, and TNFalpha mRNA levels 2 h post-LPS in the brain regions analyzed. Taken together, these findings suggest that adequate intake of dietary alpha-T and selenium may help promote recovery from gram-negative bacterial infection in the aged.

Aging↗
PubMed2004

Proinflammatory cytokine impairment of insulin-like growth factor I-induced protein synthesis in skeletal muscle myoblasts requires ceramide.

GH and IGF-I control over 80% of postnatal growth. We recently established that TNFalpha impairs the ability of IGF-I to increase protein synthesis and promote expression of myogenin in myoblasts. Here we extend these results by showing that ceramide, a second messenger in both TNFalpha and IL-1beta receptor signaling pathways, is a key downstream sphingosine-based lipid that leads to IGF-I resistance. A cell-permeable ceramide analog, C2-ceramide, inhibits IGF-I-induced protein synthesis by 65% and blocks the ability of IGF-I to increase expression of two key myogenic factors, myogenin and MyoD. Identical results were obtained with both TNFalpha and IL-1beta (1 ng/ml). Consistent with these data, neutral sphingomyelinase (N-SMase), an enzyme that catalyzes formation of ceramide from sphingomyelin, blocks IGF-I-induced protein synthesis and expression of both myogenin and MyoD. The possibility that cytokine-induced ceramide production is required for disruption of IGF-I biologic activity was confirmed by treating C2C12 myoblasts with inhibitors of all three ceramide-generating pathways. A N-SMase inhibitor, glutathione, as well as an acidic sphingomyelinase (A-SMase) inhibitor, D609, reverse the cytokine inhibition of IGF-I-induced protein synthesis by 80% and 45%, respectively. Likewise, an inhibitor of de novo ceramide synthesis, FB1, causes a 50% inhibition. Similarly, all three inhibitors significantly impair the ability of both TNFalpha and IL-1beta to suppress IGF-I-driven expression of myogenin. These experiments establish that ceramide, derived both from sphingomyelin and de novo synthesis, is a key intermediate by which proinflammatory cytokines impair the ability of IGF-I to promote protein synthesis and expression of critical muscle-specific transcription factors.

Animals↗
PubMed2004

IL-1beta suppresses prolonged Akt activation and expression of E2F-1 and cyclin A in breast cancer cells.

Cell cycle aberrations occurring at the G(1)/S checkpoint often lead to uncontrolled cell proliferation and tumor growth. We recently demonstrated that IL-1beta inhibits insulin-like growth factor (IGF)-I-induced cell proliferation by preventing cells from entering the S phase of the cell cycle, leading to G(0)/G(1) arrest. Notably, IL-1beta suppresses the ability of the IGF-I receptor tyrosine kinase to phosphorylate its major docking protein, insulin receptor substrate-1, in MCF-7 breast carcinoma cells. In this study, we extend this juxtamembrane cross-talk between cytokine and growth factor receptors to downstream cell cycle machinery. IL-1beta reduces the ability of IGF-I to activate Cdk2 and to induce E2F-1, cyclin A, and cyclin A-dependent phosphorylation of a retinoblastoma tumor suppressor substrate. Long-term activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, but not the mammalian target of rapamycin or mitogen-activated protein kinase pathways, is required for IGF-I to hyperphosphorylate retinoblastoma and to cause accumulation of E2F-1 and cyclin A. In the absence of IGF-I to induce Akt activation and cell cycle progression, IL-1beta has no effect. IL-1beta induces p21(Cip1/Waf1), which may contribute to its inhibition of IGF-I-activated Cdk2. Collectively, these data establish a novel mechanism by which prolonged Akt phosphorylation serves as a convergent target for both IGF-I and IL-1beta; stimulation by growth factors such as IGF-I promotes G(1)-S phase progression, whereas IL-1beta antagonizes IGF-I-induced Akt phosphorylation to induce cytostasis. In this manner, Akt serves as a critical bridge that links proximal receptor signaling events to more distal cell cycle machinery.

Breast Neoplasms↗
PubMed2004

IL-1beta impairs insulin-like growth factor i-induced differentiation and downstream activation signals of the insulin-like growth factor i receptor in myoblasts.

Proinflammatory cytokines are elevated in disorders characterized by muscle wasting and weakness, such as inflammatory myopathies and AIDS wasting. We recently demonstrated that TNF-alpha impairs the ability of insulin-like growth factor (IGF)-I to promote protein synthesis in muscle precursor cells. In this study we extend these findings by showing that low concentrations of IL-1beta impair IGF-I-dependent differentiation of myoblasts, as assessed by expression of the muscle specific protein, myosin heavy chain. In the absence of exogenous IGF-I, IL-1beta (1 ng/ml) did not impair muscle cell development. However, in the presence of IGF-I, 100-fold lower concentrations of IL-1beta (0.01 ng/ml) significantly suppressed myoblast differentiation, protein synthesis, and myogenin expression. Increasing IL-1beta to 1 ng/ml completely blocked the anabolic actions of IGF-I in murine C(2)C(12) myoblasts. Similarly, IL-1beta inhibited IGF-I-stimulated protein synthesis in primary porcine myoblasts. IL-1beta impaired the actions of IGF-I at a point distal to the IGF receptor, and this was not due to IL-1beta-induced cell death. Instead, IL-1beta inhibited the ability of IGF-I to phosphorylate tyrosine residues on both of its downstream docking proteins, insulin receptor substrate 1 and insulin receptor substrate 2. These data establish that physiological concentrations of IL-1beta block the ability of IGF-I to promote protein synthesis, leading to reduced expression of the myogenic transcription factor, myogenin, and the subsequent development of more mature differentiated cells that express myosin heavy chain. Collectively, the results are consistent with the notion that very low concentrations of IL-1beta significantly impair myogenesis, but they are unable to do so in the absence of the growth factor IGF-I.

Animals↗
PubMed2004

Tumor necrosis factor alpha inhibits insulin-like growth factor I-induced hematopoietic cell survival and proliferation.

Proinflammatory cytokines, such as TNFalpha and IL-1beta, are both cytostatic and cytotoxic. In contrast, IGF-I promotes proliferation and survival of hematopoietic progenitor cells. In this report, we establish that both the cytostatic and cytotoxic activity of TNFalpha on murine myeloid progenitor cells is only evident in the presence of IGF-I. We first confirmed that IGF-I (100 ng/ml) increases DNA synthesis and reduces apoptosis in murine myeloid progenitor cells induced to die by growth factor withdrawal. TNFalpha inhibits, in a dose-dependent fashion from 0.1 to 10 ng/ml, both activities of IGF-I. TNFalpha activity was not detected in the absence of IGF-I. Another proinflammatory cytokine, IL-1beta, did not inhibit IGF-I-induced activity in murine factor-dependent cell progenitor-1/Mac-1 cells. However, the ability of TNFalpha to impair IGF-I-induced DNA synthesis in human promyeloid cells extends to IL-1beta. Statistically significant inhibition of all these events occurs at very low concentrations of 1 ng/ml or less. These results support the general concept that proinflammatory cytokines impair the actions of hormones on hematopoietic cells, leading to IGF-I receptor resistance.

Animals↗
PubMed2004

From hormones to immunity: the physiology of immunology.

Discoveries in the physiology of immunology have increased at an increasing rate during the past two decades. It is now recognized that the immune system is just another physiological system that regulates, and is regulated by, other physiological systems such as the brain. These advances make it clear that recent findings in genomic biology must be interpreted in the context of the environment in which animals and humans live. Lack of a strong genetic basis for significant human mental health disorders, such as major depression, points to the critical importance of interactions. Several examples of environmental x genetic x disease interactions are presented. Regulation of cells of the hematopoietic lineage by two genes that control over 80% of postnatal growth, growth hormone and IGF-I, are then highlighted. The reciprocal relationship of how proinflammatory cytokines from the immune system regulate the growth hormone/IGF-I axis is also summarized. Particular emphasis is placed upon TNFalpha-induced IGF-I resistance in neurons, muscle cells and epithelial cells. This cytokine regulation of hormone action may ultimately be more important for human and animal health than direct effects of growth hormone and IGF-I on hematopoietic cells. Wasting of AIDS patients is given as an important clinical example of how TNFalpha from an activated immune system reduces IGF-I sensitivity in multiple physiologic systems, including muscle, nervous and hematopoietic tissues.

Animals↗
PubMed2004

alpha-Tocopherol reduces lipopolysaccharide-induced peroxide radical formation and interleukin-6 secretion in primary murine microglia and in brain.

The purpose of this study was to determine if alpha-tocopherol-a reactive oxygen species (ROS) scavenging agent-inhibits LPS-induced oxidative stress and interleukin-6 (IL-6) production in murine microglia and brain. LPS increased intracellular peroxides and IL-6 in a dose-dependent fashion in primary microglia. The LPS-induced increase in ROS and IL-6 was reduced by pretreatment of alpha-tocopherol. Intraperitoneal injection (i.p.) of LPS induced lipid peroxidation and IL-6 in brain. Importantly, three daily injections (20 mg) of alpha-tocopherol increased brain alpha-tocopherol and decreased LPS-induced lipid peroxidation and IL-6 in brain. Taken together, these data indicate that alpha-tocopherol can mitigate inflammatory cytokine production in the brain.

Animals↗
PubMed2004

Alpha-tocopherol attenuates lipopolysaccharide-induced sickness behavior in mice.

Antioxidants protect cells from oxidative damage and reduce lipopolysaccharide (LPS)-induced expression of inflammatory cytokines. Because inflammatory cytokines induce sickness behavior, we hypothesized that antioxidants, namely alpha-tocopherol (alpha-T) and selenium would inhibit sickness behavior caused by LPS. In an initial study, mice were injected intraperitoneal (i.p.) with vehicle, 2, or 20mg alpha-T for 3 consecutive days and then challenged with vehicle, 1, 10, or 100 microg of LPS. Sickness behavior was quantified by measuring social exploratory behavior. Vehicle pretreated mice injected with LPS showed a marked reduction in social behavior at 4h (p < .01). However, sickness behavior induced by the lowest dose of LPS was partially or completely blocked by 2 or 20mg alpha-T, respectively. alpha-T did not prevent sickness from higher doses of LPS. In a second study, mice were fed AIN93-M modified diets containing 10, 75, and 500 mg alpha-T/kg and 0.05, 0.15, and 2mg selenium/kg for 8 weeks and then challenged with saline or LPS (1 microg). The highest concentration of dietary alpha-T and selenium tended (p = .1) to reduce LPS-induced sickness behavior. Mice fed diets low in antioxidants had reduced plasma alpha-T levels and glutathione peroxidase activity (p = .08 and p < .01, respectively) and elevated liver thiobarbituric acid reactive substances (p < .001) 24h post LPS. Collectively, these data indicate that alpha-T improved the oxidative status after exposure to LPS, which may explain its ability to ameliorate symptoms of sickness.

Analysis of Variance↗
PubMed2004

Conditioned taste aversion with lipopolysaccharide and peptidoglycan does not activate cytokine gene expression in the spleen and hypothalamus of mice.

Several reports show that behavioural and physiological components of the acute phase reaction can be conditioned. However, the mechanisms responsible for these effects remain obscure. The underlying assumption that the changes observed in conditioned animals are dependent on a conditioned production of cytokines has never been demonstrated. In the present study, the possibility of conditioning the production of cytokines or molecules implicated in their signalling pathways was tested by submitting mice to conditioned taste aversion with a new saccharin taste paired with intraperitoneal (i.p.) injections of lipopolysaccharide (LPS, 0.83 microg/g) or peptidoglycan (PGN, 20 microg/g). After two conditioning sessions, conditioned mice developed a clear aversion to saccharine that was not associated with activation of genes of the cytokine network either at the periphery, or in the hypothalamus, as demonstrated by a macroarray approach and confirmed by real time RT-PCR. In contrast, there was an activation of the genes coding for nuclear factor kappa B (NFkappaB) and mitogen activated protein kinase (MAPK) signalling pathways in the spleen and to a lesser extent in the hypothalamus. This modulation of the NFkappaB and MAPK signalling pathways is interpreted in terms of a possible conditioned sensitisation of the immune system.

Analysis of Variance↗