Dynamics of the cytokine messenger RNA expression pattern in the liver of baboons infected with Schistosoma mansoni

Periovular granulomas are the major lesions in baboons infected with Schistosoma mansoni. Temporal Northern blot analysis of cytokine messenger RNA (mRNA) expression in granulomatous baboon livers demonstrated tissue-specific expression. Interleukin 1 beta (IL-1beta, IL-6, tumor necrosis factor alpha, and migration inhibitory factor (MIF) mRNAs were expressed strongly at week 6 of infection and decayed thereafter, whereas interferon gamma (IFN-gamma), IL-2, IL-10, and IL-12 mRNAs were first expressed at week 12, with IFN-gamma and IL-12 mRNA expression persisting until week 17. IL-4 and IL-5 mRNAs first appeared at week 12, with IL-4 persisting unchanged and IL-5 increasing by week 17. Thus, egg deposition induced strong hepatic expression of proinflammatory and downregulatory cytokines. The cooccurrence of IL-2, IFN-gamma, IL-4, and IL-5 mRNAs at week 12 confirms that baboons, like humans, show a mixed type 1-type 2 cytokine response. When granulomas had become smaller at 17 wk, IFN-gamma, IL-4, and IL-5 were the only cytokine mRNAs that were expressed strongly, implicating them in granuloma modulation. The early expression of MIF mRNA and MIF's role as the main counterregulator of glucocorticoid immunosuppression ties in with our earlier demonstrations of circulating adrenal steroids changing with the progression of schistosomiasis in baboons and of proinflammatory cytokine mRNA expression in the hypothalamic-pituitary-adrenal axis tissues of infected baboons. Together, these data imply neuroendocrinological influences on disease progression in schistosomiasis.     

Effect of TNF-alpha on prolactin secretion from rat anterior pituitary and dopamine release from the hypothalamus: comparison with the effect of interleukin-1 beta.

The effects of human recombinant interleukin-1 beta and -6 and tumor necrosis factor-alpha (TNF-alpha) on the releases of PRL and dopamine were examined using monolayer cultures of rat pituitary cells and hypothalamic cells. The release of PRL from rat pituitary cells in 30 min was increased about 2-fold (p less than 0.05) by 10(5) U/l interleukin-1 beta, 10(5) U/l interleukin-6 or 100 micrograms/l TNF-alpha. TNF-alpha at 100 micrograms/l significantly increased PRL release within 5 min incubation and this effect continued throughout the next 30 min of incubation. Incubation for 5 min with TNF-alpha caused dose-dependent stimulation of PRL release. These cytokines did not modulate [3H]-dopamine release from primary cultures of hypothalamic cells. These results suggest that these cytokines stimulate PRL release directly at the pituitary gland, without modifying the release of dopamine from the hypothalamus.     

Tumor necrosis factor and interleukin-1 induce activin A gene expression in a human bone marrow stromal cell line.

Activin A, a homodimer of the beta A chain, regulates hematopoiesis. In a human bone marrow-derived stromal cell line, KM-102, phorbol myristate acetate, tumor necrosis factor-alpha and interleukin-1 beta induced great increases in beta A chain mRNA levels and production of activin A activities. The phorbol ester-induced beta A chain gene expression was inhibited by cycloheximide and down regulation of protein kinase C, whereas the cytokine-induced expression was little affected by these treatments. These results indicate that the inflammatory cytokines directly stimulate beta A chain gene expression via protein kinase C-independent pathways.     

Role of interleukin-1 in stress responses

Recently, the central roles of interleukin-1 (IL-1) in physical stress responses have been attracting attention. Stress responses have been characterized as central neurohormonal changes, as well as behavioral and physiological changes. Administration of IL-1 has been shown to induce effects comparable to stress-induced changes. IL-1 acts on the brain, especially the hypothalamus, to enhance release of monoamines, such as norepinephrine, dopamine, and serotonin, as well as secretion of corticotropin-releasing hormone (CRH). IL-1-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis in vivo depends on secretion of CRH, an intact pituitary, and the ventral noradrenergic bundle that innervates the CRH-containing neurons in the paraventricular nucleus of the hypothalamus. Recent studies have shown that IL-1 is present within neurons in the brain, suggesting that IL-1 functions in neuronal transmission. We showed that IL-1 in the brain is involved in the stress response, and that stress-induced activation of monoamine release and the HPA axis were inhibited by IL-1 receptor antagonist (IL-1Ra) administration directly into the rat hypothalamus. IL-1Ra has been known to exert a blocking effect on IL-1 by competitively inhibiting the binding of IL-1 to IL-1 receptors. In the latter part of this review, we will attempt to describe the relationship between central nervous system diseases, including psychological disorders, and the functions of IL-1 as a putative neurotransmitter.     

Stimulation of ACTH release by human interleukin-1 beta, but not by interleukin-1 alpha, in conscious, freely-moving rats

Ever since two distinct molecules of human interleukin-1 (termed interleukin-1 alpha and interleukin-1 beta) were cloned, sequenced and expressed, it has been a matter of investigation whether these two forms of interleukin-1 possess an identical spectrum of biological activities. Our current studies of interleukin-1 and its involvement in the hypothalamic-pituitary-adrenal axis have indicated that there is a clear-cut differential response to interleukin-1 alpha and interleukin-1 beta. The intravenous injection of human recombinant interleukin-1 beta significantly increased the plasma levels of adrenocorticotropic hormone in a dose-related manner, whereas interleukin-1 alpha did not. This observation suggests for the first time that the two members of the interleukin-1 family may have a different spectrum of biological actions.     

Hypothalamic releasing hormones mediating the effects of interleukin-1 on sleep

There is a substantial literature describing the interactions between the endocrine and immune systems. Although such interactions are less well known within the brain, one major brain function altered during inflammation and infection and by several endocrine hormones is sleep. Pathological disturbances, be they inflammation, infectious disease, and/or sleep deprivation, result in altered hypothalamus-pituitary function and cytokine metabolism. In respect to hormone secretion from the pituitary, cytokines are now recognized to play an important role in modulating the neuroendocrine system. Changes in sleep provide a useful illustration of the interactions between cytokines and the hypothalamus-pituitary axis. Evidence linking interleukin-1 (IL-1) to growth hormone releasing hormone and to corticotropin releasing hormone in regard to their effects on sleep is reviewed.     

Interleukin-10 Regulated Gene Expression in Cells of Hypothalamic-Pituitary-Adrenal Axis Origin

1. Aim: The hypothalamic-pituitary-adrenal (HPA) axis is a mediator for interactions between the immune and neuroendocrine systems. Pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) have been shown to activate the HPA axis. Recently, interleukin-10, an important anti-inflammatory cytokine in the immune system, has been shown to be expressed in the central nervous system and neuroendocrine system. Little is known, however, about IL-10’s functions in the HPA axis. 2. Methods: The Affymetrix DNA microarray (mouse genome U74Av2 Probe Array) was conducted to determine the gene expression profile regulated by IL-10 in cells of HPA axis origin. 3. Results: In this study, we analyzed gene expression regulated by IL-10 in cells derived from the HPA axis. The results showed that quorums of genes are modulated by IL-10 in these neuroendocrine cells. 4. Conclusions: These findings will provide a valuable repository to aid in understanding IL-10’s functions in the HPA axis at the molecular level.     

Inhibition of brain proinflammatory cytokine synthesis reduces hypothalamic excitation in rats with ischemia-induced heart failure

The expression of proinflammatory cytokines increases in the hypothalamus of rats with heart failure (HF). The pathophysiological significance of this observation is unknown. We hypothesized that hypothalamic proinflammatory cytokines upregulate the activity of central neural systems that contribute to increased sympathetic nerve activity in HF, specifically, the brain renin-angiotensin system (RAS) and the hypothalamic-pituitary-adrenal (HPA) axis. Rats with HF induced by coronary ligation and sham-operated controls (SHAM) were treated for 4 wk with a continuous intracerebroventricular infusion of the cytokine synthesis inhibitor pentoxifylline (PTX, 10 microg/h) or artificial cerebrospinal fluid (VEH). In VEH-treated HF rats, compared with VEH-treated SHAM rats, the hypothalamic expression of proinflammatory cytokines was increased, along with key components of the brain RAS (renin, angiotensin-converting enzyme, angiotensin type 1 receptor) and corticotropin-releasing hormone, the central indicator of HPA axis activation, in the paraventricular nucleus (PVN) of the hypothalamus. The expression of other inflammatory/excitatory mediators (superoxide, prostaglandin E(2)) was also increased, along with evidence of chronic neuronal excitation in PVN. VEH-treated HF rats had higher plasma levels of norepinephrine, ANG II, interleukin (IL)-1beta, and adrenocorticotropic hormone, increased left ventricular end-diastolic pressure, and increased wet lung-to-body weight ratio. With the exception of plasma IL-1beta, an indicator of peripheral proinflammatory cytokine activity, all measures of neurohumoral excitation were significantly lower in HF rats treated with intracerebroventricular PTX. These findings suggest that the increase in brain proinflammatory cytokines observed in rats with ischemia-induced HF is functionally significant, contributing to neurohumoral excitation by activating brain RAS and the HPA axis.     

Tumour necrosis factor-alpha and interleukin-8 inhibit neutrophil migration in vitro and in vivo

Pretreatment of human neutrophils with recombinant tumour necrosis factor-alpha (rTNF-alpha) and/or interleukin-8 (rIL-8), but not with either transforming growth factor-beta, interleukin-6 or interferon-gamma, rendered these cells less responsive to FMLP, in microchemotaxis assays. This inhibitory effect was dose dependent and more powerful when neutrophils were pretreated with a mixture of both cytokines. Intravenous injection of human rIL-8 (hrIL-8) and/or murine rTNF-alpha (mrTNF-alpha) also significantly reduced in vivo neutrophil migration into peritoneal cavities of rats stimulated with carrageenan. These data suggest that the defect in neutrophil migration during septicaemia or endotoxaemia may be the result of the continuous release of IL-8 and TNF-alpha into the circulation. Thus, either the selective control or blockade of releasing of these cytokines as well as of its effects on neutrophils may be clinically useful in reestablishing the cell defence mechanisms.     

Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-induced ceramide production through the activation of phosphatidylinositol 3-kinase

Ceramide produced by hydrolysis of plasma membrane sphingomyelin (SM) in different cells including brain cells in response to proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta)] plays an important role in coordinating cellular responses to stress, growth suppression, and apoptosis. The present study underlines the importance of IL-10 and IL-13, cytokines with potent antiinflammatory properties, in inhibiting the proinflammatory cytokine (TNF-alpha and IL-1beta)-mediated degradation of SM to ceramide in rat primary astrocytes. Treatment of rat primary astrocytes with TNF-alpha or IL-1beta led to rapid degradation of SM to ceramide, whereas IL-10 and IL-13 by themselves were unable to induce the degradation of SM to ceramide. Interestingly, both IL-10 and IL-13 prevented proinflammatory cytokine-induced degradation of SM to ceramide. Both IL-10 and IL-13 caused rapid activation of phosphatidylinositol (PI) 3-kinase, and inhibition of that kinase activity by wortmannin and LY294002 potently blocked the inhibitory effect of IL-10 and IL-13 on proinflammatory cytokine-mediated induction of ceramide production. This study suggests that the inhibition of proinflammatory cytokine-mediated degradation of SM to ceramide by IL-10 and IL-13 is mediated through the activation of PI 3-kinase. As ceramide induces apoptosis and IL-10 and IL-13 inhibit the induction of ceramide production, we examined the effect of IL-10 and IL-13 on proinflammatory cytokine-mediated apoptosis. Inhibition of TNF-alpha-induced apoptosis by IL-10 and IL-13 suggests that the antiapoptotic nature of IL-10 and IL-13 is probably due to the inhibition of ceramide production.     

Macrophage migration inhibitory factor exhibits a pronounced circadian rhythm relevant to its role as a glucocorticoid counter-regulator

In humans, maximal expression of T helper 1 cytokines coincide with the nocturnal nadir of plasma cortisol, whereas T helper 2 cytokine responses are dominant during day-time. The pro-inflammatory cytokine, macrophage migration inhibitory factor counter-regulates glucocorticoid-mediated immune suppression. To determine the relationship between cortisol and macrophage migration inhibitory factor, healthy volunteers had blood drawn hourly for 24 h for measurement of plasma cortisol and basal- and stimulated-macrophage migration inhibitory factor. Similar to cortisol, macrophage migration inhibitory factor peaked during the late morning whereas interferon-gamma, tumour necrosis factor-alpha, interleukin-1 and interleukin-12 demonstrated a nocturnal peak. After oral cortisone, plasma macrophage migration inhibitory factor rose 2-4-fold, whereas the other cytokines decreased. There was no correlation between cortisol during the insulin tolerance test and plasma macrophage migration inhibitory factor. The late morning peak of macrophage migration inhibitory factor, by antagonizing cortisol-mediated pro-inflammatory cytokine suppression may prolong the duration of early morning inflammation. These observations explain the beneficial role of macrophage migration inhibitory factor neutralization in models of inflammatory arthritis.     

Regulation of gonadotropin-releasing hormone (GnRH) gene expression in hypothalamic neuronal cells

Summary 1. Gonadotropin-releasing hormone (GnRH) is the hypothalamic releasing factor that controls pituitary gonadotropin subunit gene expression and indirectly gametogenesis and steroidogenesis from the gonad, which results in reproductive competence.2. GnRH is synthesized in only about 1000 neurons in the hypothalamus and released in an episodic fashion down the median eminence to regulate gonadotropin biosynthesis.3. Although much is known about the secretory dynamics of GnRH release, little is known about the pretranslational control of GnRH biosynthesis due to lack of appropriate model systems. The recent availability of immortalized neuronal cell lines that produce GnRH allows investigators for the first time to begin to dissect the factors that directly regulate GnRH gene expression.4. This article reviews the current state of knowledge concerning the mechanisms that direct tissue-specific and peptide hormone control of GnRH biosynthesis.     

Cloning and expression of TNF-alpha, IL-1beta and COX-2 in an anadromous and landlocked strain of Atlantic salmon (Salmo salar L.) during the smolting period

The parr-smolt transformation involves complex modulation of immune parameters, affecting both cell populations and humoral factors. The expression of cytokines was studied in salmon cells and tissues during this period using an anadromous and a landlocked freshwater resident dwarf strain of Atlantic salmon (Salmo salar L.). The constitutive activity of three immunoregulatory genes encoding the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) and the cyclo-oxygenase (COX) isoform COX-2 was investigated in head kidney, spleen and gill tissue from healthy, unvaccinated fish by real-time PCR. The TNF-alpha gene was generally lower expressed than COX-2 and IL-1beta1, which were approximately expressed at equal levels and constitutive expression was seen for COX-2 and IL-1beta1 in all tissues examined and at all sampling dates. The expression of all three genes in head kidney and spleen tissue seemed to be highest at the sampling in May for both strains around the time of seawater transfer suggesting an influence of smolting related hormones on cytokine expression. The gill tissue experienced the highest expression of IL-1beta1 and COX-2 at all sampling dates indicating that this organ is immunologically important.     

Estrogen reduces pro-inflammatory cytokines in rodent adipose tissue: studies in vivo and in vitro.

Obesity is associated with an increased risk of developing insulin resistance, Type 2 diabetes, and cardiovascular disease. Reports have suggested that adipose tissue-derived cytokines such as tumor necrosis factor-alpha, interleukin-6 and interleukin-8 could be involved in the development of these health complications. Since estrogen has been suggested to attenuate the development of atherosclerosis and cardiovascular disease, we investigated whether ovariectomy affected the production and release of these three adipose tissue-derived cytokines with and without estrogen replacement in vivo and in vitro. Female Wistar rats were submitted to either a) ovariectomy, b) ovariectomy and estrogen replacement, or c) sham operation. After five months, animals were sacrificed and parametrial adipose tissue was removed and incubated for up to 24 hours with either interleukin-1beta (IL-1beta) (5 micro g/l), dexamethasone (50 nM) or estrogen (50 nM). Ovariectomy significantly increased interleukin-6 gene expression (p < 0.05) as well as interleukin-8 protein levels (p < 0.05) and gene expression (p < 0.05) in the adipose tissue, and estrogen replacement significantly reversed this increase (p < 0.05). However, no direct effects of estrogen were found in in vitro adipose tissue incubations. Neither ovariectomy nor estrogen replacement had any effects on tumor necrosis factor-alpha protein levels or gene expression. In conclusion, estrogen-deficient rats were found to have increased production of interleukin-6 and interleukin-8, which could be attenuated by estrogen-replacement. Since estrogen is suggested to be anti-atherosclerotic, this effect might be caused by a reduction in cytokine production from the adipose tissue.