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Neonatal glucocorticoid (GC) treatment is used to prevent bronchopulmonary dysplasia (BPD) in prematurely born babies. In the 1990s, treatment regimens with relatively high doses of dexamethasone (DEX) were common. As an alternative, hydrocortisone (HC) was used. Earlier, we compared long-term effects of both GCs in children aged 7-10 and detected adverse effects of neonatal DEX treatment, but not of HC, on a range of outcomes. The aim of the current cohort study was to investigate whether long-term effects of neonatal DEX were maintained and whether effects of HC remained absent at adolescent age (14-17years). We compared 71 DEX-treated and 67 HC-treated adolescents. In addition, 71 adolescents who were not neonatally treated with GCs participated. All were born <32weeks of gestation. DEX-treated girls showed increased adrenocorticotropic hormone (ACTH) and cortisol responses in the Trier Social Stress Test. The cortisol awakening response was lower in HC-treated participants compared to untreated participants. Negative feedback function of the HPA-axis in the dexamethasone suppression test did not differ between groups. In contrast to our observations at the age of 7-10years, we did not observe group differences in mitogen-induced cytokine production at the age of 14-17years. DEX-treated girls showed more social problems and anxious/depressed behavior than HC-treated girls. Untreated girls showed more problem behavior as well. In conclusion, our results suggest that, especially in girls, neonatal DEX has a programming effect on the HPA-axis and on the ability to adjust to the environment. The loss of group differences on immune system measures indicate that potentially negative effects detected at a younger age subsided., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Combat stress exposed soldiers may respond to post-deployment stressful life events (SLE) with increases in symptoms of posttraumatic stress disorder (PTSD), consistent with a model of stress sensitization. Several lines of research point to sensitization as a model to describe the relations between exposure to traumatic events, subsequent SLE, and symptoms of PTSD. Based on previous findings we hypothesized that immune activation, measured as a high in vitro capacity of leukocytes to produce cytokines upon stimulation, underlies stress sensitization., Methods: We assessed mitogen-induced cytokine production at 1 month, SLE at 1 year, and PTSD symptoms from 1 month up to 2 years post-deployment in soldiers returned from deployment to Afghanistan (N=693). Exploratory structural equation modeling as well as latent growth models were applied., Results: The data demonstrated significant three-way interaction effects of combat stress exposure, cytokine production, and post-deployment SLE on linear change in PTSD symptoms over the first 2 years following return from deployment. In soldiers reporting high combat stress exposure, both high mitogen-stimulated T-cell cytokine production and high innate cytokine production were associated with increases in PTSD symptoms in response to post-deployment SLE. In low combat stress exposed soldiers as well as those with low cytokine production, post-deployment SLE were not associated with increases in PTSD symptoms., Conclusion: High stimulated T-cell and innate cytokine production may contribute to stress sensitization in recently deployed, high combat stress exposed soldiers. These findings suggest that detecting and eventually normalizing immune activation may potentially complement future strategies to prevent progression of PTSD symptoms following return from deployment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Studies suggest that cardiac resynchronization therapy (CRT) can induce a decrease in brain natriuretic peptide (BNP) and systemic inflammation, which may be associated with CRT-response. However, the evidence is inconclusive. We examined levels of BNP and inflammatory markers from pre-CRT implantation to 14months follow-up in CRT-responders and nonresponders, defined by two response criteria., Methods: We studied 105 heart failure patients implanted with a CRT-defibrillator (68% men; age=65.4±10.1years). The objective CRT-response was defined as a reduction of ⩾15% in left ventricular end systolic volume; subjective CRT-response was defined as an improvement of ⩾10 points in patient-reported health status assessed with the Kansas City Cardiomyopathy Questionnaire. Plasma BNP and markers of inflammation (CRP, IL-6, TNFα, sTNFr1 and sTNFr2) were measured at three time points., Results: Pre-implantation concentrations of TNFα were significantly lower for subjective responders compared to nonresponders (p=.05), but there was no difference in BNP and the other inflammatory markers at baseline. Objective CRT-response was significantly associated with lower BNP levels over time (F=27.31, p<.001), and subjective CRT-response with lower TNFα levels (F=5.67, p=.019)., Conclusion: Objective and subjective response to CRT was associated with lower levels of BNP and TNFα, respectively, but not with other markers of inflammation. This indicates that response to CRT is not automatically related to a stronger overall decrease in inflammation. Large-scale studies are warranted that further examine the relation between the clinical effects of CRT on inflammatory markers, as the latter have been associated with poor prognosis in heart failure., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The molecular mechanisms determining magnitude and duration of inflammatory pain are still unclear. We assessed the contribution of G protein-coupled receptor kinase (GRK)-6 to inflammatory hyperalgesia in mice. We showed that GRK6 is a critical regulator of severity and duration of cytokine-induced hyperalgesia. In GRK6⁻/⁻ mice, a significantly lower dose (100 times lower) of intraplantar interleukin (IL)-1β was sufficient to induce hyperalgesia compared with wild-type (WT) mice. In addition, IL-1β hyperalgesia lasted much longer in GRK6⁻/⁻ mice than in WT mice (8 d in GRK6⁻/⁻ versus 6 h in WT mice). Tumor necrosis factor (TNF)-α-induced hyperalgesia was also enhanced and prolonged in GRK6⁻/⁻ mice. In vitro, IL-1β-induced p38 phosphorylation in GRK6⁻/⁻ dorsal root ganglion (DRG) neurons was increased compared with WT neurons. In contrast, IL-1β only induced activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway in WT neurons, but not in GRK6⁻/⁻ neurons. In vivo, p38 inhibition attenuated IL-1β- and TNF-α-induced hyperalgesia in both genotypes. Notably, however, whereas PI 3-kinase inhibition enhanced and prolonged hyperalgesia in WT mice, it did not have any effect in GRK6-deficient mice. The capacity of GRK6 to regulate pain responses was also apparent in carrageenan-induced hyperalgesia, since thermal and mechanical hypersensitivity was significantly prolonged in GRK6⁻/⁻ mice. Finally, GRK6 expression was reduced in DRGs of mice with chronic neuropathic or inflammatory pain. Collectively, these findings underline the potential role of GRK6 in pathological pain. We propose the novel concept that GRK6 acts as a kinase that constrains neuronal responsiveness to IL-1β and TNF-α and cytokine-induced hyperalgesia via biased cytokine-induced p38 and PI 3-kinase/Akt activation.

When the inflammatory phase of sarcoidosis has resolved, complaints of chronic fatigue frequently persist. Low-grade residual inflammatory activity may play a role in maintaining chronic fatigue. The aim of this study was to compare in vitro cytokine/chemokine production and plasma cytokine/chemokine levels between chronically fatigued and non-fatigued patients with sarcoidosis in clinical remission. Patients with sarcoidosis in clinical remission were assigned to a non-fatigued group (n=38) or a fatigued group (n=34) based on the standardized cut-off of the fatigue questionnaire Checklist Individual Strength. Cytokines/chemokines in plasma and in supernatants of whole blood cultures stimulated with either a T cell mitogen or lipopolysaccharide were quantified by multiplex analysis. Associations of cytokine/chemokine profiles with chronic fatigue were analyzed by multivariate analysis of variance and principal component analysis followed by logistic regression. Principal component analysis of T cell mitogen-induced cytokine/chemokine production identified three components that explained 76% of the variance in the cytokine/chemokine data. Logistic regression revealed that the 'Th2 cytokine'-component which mainly consists of interleukin (IL)-4, IL-5 and IL-10 was significantly and negatively associated with chronic fatigue. In addition, multivariate analysis revealed higher levels of LPS-induced IL-8 and lower levels of plasma monocyte chemoattractant protein (MCP)-1 in the fatigued group compared to the non-fatigued group. In chronically fatigued sarcoidosis patients in clinical remission, we found a cytokine/chemokine profile which is suggestive for a less competent Th2 counterbalancing capacity, that may contribute to the persistence of chronic fatigue., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is frequently diagnosed in military personnel returning from deployment. Literature suggests that MDD is associated with a pro-inflammatory state. To the best of our knowledge, no prospective, longitudinal studies on the association between development of depressive symptomatology and cytokine production by peripheral blood leukocytes have been published. The aim of this study was to investigate whether the presence of depressive symptomatology six months after military deployment is associated with the capacity to produce cytokines, as assessed before and after deployment. 1023 military personnel were included before deployment. Depressive symptoms and LPS- and T-cell mitogen-induced production of 16 cytokines and chemokines in whole blood cultures were measured before (T0), 1 (T1), and 6 (T2) months after return from deployment. Exploratory structural equation modeling (ESEM) was used for data reduction into cytokine patterns. Multiple group latent growth modeling was used to investigate differences in the longitudinal course of cytokine production between individuals with (n = 68) and without (n = 665) depressive symptoms at T2. Individuals with depressive symptoms after deployment showed higher T-cell cytokine production before deployment. Moreover, pre-deployment T-cell cytokine production significantly predicted the presence of depressive symptomatology 6 months after return. There was an increase in T-cell cytokine production over time, but this increase was significantly smaller in individuals developing depressive symptoms. T-cell chemokine and LPS-induced innate cytokine production decreased over time and were not associated with depressive symptoms. These results indicate that increased T-cell mitogen-induced cytokine production before deployment may be a vulnerability factor for development of depressive symptomatology in response to deployment to a combat-zone. In addition, deployment to a combat-zone affects the capacity of T-cells and monocytes to produce cytokines and chemokines until at least 6 months after return.

Objective: To elucidate the impact of ovarian stimulation on the intrauterine milieu represented by the cytokine, chemokine, and growth factor profile in endometrial secretions aspirated before embryo transfer., Design: Prospective cohort study., Setting: Fertility center in tertiary referral university hospital., Patient(s): Forty-two patients undergoing ovarian stimulation with GnRH analogues were recruited. They participated in both a natural and an ovarian-stimulated cycle for within patient comparisons., Intervention(s): Endometrial secretion aspiration was performed immediately before embryo transfer., Main Outcome Measure(s): The concentrations of 17 mediators known to be involved in human embryo implantation were assessed by multiplex immunoassay., Result(s): After correction for multiple testing, significantly higher concentrations of interleukin (IL)-1β, IL-5, IL-10, IL-12, IL-17, tumor necrosis factor (TNF)-α, heparin-binding epidermal growth factor (HbEGF), eotaxin, and dickkopf homologue-1 were present in endometrial secretions obtained in stimulated compared with natural cycles., Conclusion(s): Endometrial secretion analysis provides a novel means of investigating the effect of ovarian stimulation on the intrauterine milieu. The in vivo milieu encountered by the embryo after transfer is significantly altered by ovarian stimulation., (Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The objective of this prospective cohort study was to elucidate whether bacterial vaginosis (BV) is associated with a pro-inflammatory endometrial secretion cytokine profile and whether there is a relationship between BV and the concentrations of a number of key regulatory cytokines, chemokines and growth factors. A total of 198 women undergoing IVF treatment were included. Prior to embryo transfer, participants underwent screening for BV according to Nugent criteria by a Gram-stained cervical smear. The concentrations of 17 soluble mediators of human implantation were measured by multiplex immunoassay in endometrial secretions aspirated prior to embryo transfer. Seventeen (8.6%) women had BV (Nugent score >6). Multivariable logistic regression showed a significant positive association between interleukin-beta and the presence of BV (P=0.011; Nugent score >6 versus 6) and a significant negative association between eotaxin and BV (P=0.003). No significant differences were found in the ratios of distinct pro- and anti-inflammatory cytokines in endometrial secretions from women with or without BV. In conclusion, BV is associated with higher concentrations of interleukin-beta in endometrial secretions compared with women without BV. However, no distinct difference in pro- and anti-inflammatory profiles is present. An effect on endometrial receptivity is unlikely., (2010. Published by Elsevier Ltd.)

Background: The study of human endometrial-embryonic interactions is complicated by the disruptive impact of endometrial sample collection on the process of implantation itself. Endometrial secretion analysis is a novel technique, non-disruptive to implantation. The primary aim of this prospective cohort study was to explore whether a cytokine profile predictive of implantation and clinical pregnancy can be identified in endometrial secretions aspirated immediately prior to embryo transfer following IVF., Methods: Endometrial secretions, aspirated immediately prior to embryo transfer from 210 women undergoing IVF, were analyzed using a multiplex immunoassay for 17 soluble regulators of implantation, namely interleukin (IL)-1beta, IL-5, IL-6, IL-10, IL-12, IL-15, IL-17, IL-18, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, macrophage migration inhibitory factor, eotaxin, IFN-gamma-inducible 10 kDa protein (IP-10), monocyte chemo-attractant protein-1 (MCP-1), Dickkopf homolog 1, heparin-binding epidermal growth factor and vascular endothelial growth factor (VEGF). In order to detect implantation, daily urine samples were collected after embryo transfer, and human Chorionic Gonadotropin (hCG) concentrations were analyzed by an immunoassay., Results: Multivariable logistic regression analysis revealed significant associations (negative and positive association, respectively) between MCP-1 (P = 0.005) and IP-10 (P = 0.037) levels and implantation, and between IL-1beta (P = 0.047) and TNF-alpha (P = 0.023) levels and clinical pregnancy. The predictive value for pregnancy of IL-1beta and TNF-alpha was observed to be equivalent and additive to that of embryo quality., Conclusions: Endometrial secretion cytokine profiling offers a novel, non-disruptive approach to study the role of the endometrium in human embryo implantation and identifies a profile which appears to be conducive to clinical pregnancy., Clinical Trial Registration: www.clinicaltrials.gov (nCT00264992).

Investigation of human embryo implantation requires a non-disruptive means of studying the endometrium during the window of implantation. This study describes a novel approach of cytokine profiling in endometrial secretions. Endometrial secretions aspirated prior to embryo transfer from 210 women undergoing IVF or intracytoplasmic sperm injection were analysed by a multiplex immunoassay. Ten mediators [interleukin (IL)-1beta, IL-6, IL-12, IL-18, tumour necrosis factor-alpha, macrophage migration inhibitory factor, eotaxin, monocyte chemotactic protein-1, interferon-gamma inducible protein-10, vascular endothelial growth factor] were detectable in 90-100% of the samples. Heparin-binding epidermal growth factor, IL-5, IL-17, IL-10, Dickkopf homologue-1 and IL-15 were detected in 23-76%, whereas interferon-gamma was not detectable in any of the samples. To assess possible contamination of samples, cervical mucus was also aspirated for comparative analysis in 22 women. The endometrial cytokine profile differed significantly from cervical mucus. Pregnancy rates of the study participants who underwent endometrial secretion aspiration were compared with 210 controls matched for important prognostic variables; no significant differences were found. In conclusion, cytokine profiling in endometrial secretion offers an objective, non-disruptive means of analysing the in-vivo milieu encountered by the embryo and offers a new and potentially valuable approach to studying the endometrial factor in human embryo implantation.

Successful implantation is an absolute requirement for the reproduction of species, including humans. The process by which a foreign blastocyst is accepted by the maternal endometrium is complex and requires interplay of many systems. Implantation occurs during the putative implantation window, in which the maternal endometrium is ready to accept the blastocyst, which on the other hand, also plays a specific role. It produces cytokines and chemokines and expresses adhesion molecules and certain classes of MHC molecules. We review the most important players in implantation. Concerning the cytokines, the establishment of controlled aggression is key; an excess of pro- or anti-inflammation is detrimental to pregnancy outcome. Chemokines control the orientation of the embryo. The adhesion molecules are necessary to establish the required physical interaction between mother and blastocyst. Finally, immune cells and in particular, uterine NK and regulatory T cells are pivotal in inducing tolerance to the blastocyst. The aim of this review is to discuss mechanisms at play and their relative importance to the establishment of pregnancy.

Hostility is a risk factor for adverse health outcomes as diverse as cardiovascular disease and post-traumatic stress disorder (PTSD). Cytokines have been suggested to mediate this relationship. We investigated whether in healthy men a relation existed between hostility and T-cell mitogen-induced cytokines and chemokines. Male Dutch military personnel (n=304) were included before deployment. Eleven cytokines and chemokines were measured in supernatants of T-cell mitogen-stimulated whole blood cultures by multiplex immunoassay. Factor analysis was used to identify clusters of cytokines and chemokines. In a regression analysis hostility was related to the cytokine/chemokine clusters, and the potential risk factors age, BMI, smoking, drinking, previous deployment, early life trauma and depression. Explorative factor analysis showed four functional clusters; a pro-inflammatory factor (IL-2, TNFalpha, IFNgamma), an anti-inflammatory factor (IL-4, IL-5, IL-10), IL-6/chemokine factor (IL-6, MCP-1, RANTES, IP-10), and MIF. Hostility was significantly related to decreased IL-6/chemokine secretion and increased pro- and anti-inflammatory cytokines. There was an inverse relation between age and hostility scores. Early life trauma and depression were positively and independently related to hostility as well. This study represents a novel way of investigating the relation between cytokines and psychological characteristics. Cytokines/chemokines clustered into functional factors, which were related to hostility in healthy males. Moreover this relation appeared to be independent of reported depression and early trauma.

Background and Purpose: Interactions between excitotoxic, inflammatory, and apoptotic pathways determine outcome in hypoxic-ischemic brain damage. The transcription factor NF-kappaB has been suggested to enhance brain damage via stimulation of cytokine production. There is also evidence that NF-kappaB activity is required for neuronal survival. We used the NF-kappaB inhibitor NBD, coupled to TAT to facilitate cerebral uptake, to determine the neuroprotective capacity of NF-kappaB inhibition in neonatal hypoxia-ischemia (HI) and to identify its contribution to cerebral inflammation and damage., Methods: Brain damage was induced in neonatal rats by unilateral carotid artery occlusion and hypoxia and analyzed immunohistochemically; NF-kappaB activity was analyzed by EMSA. We analyzed cytokine mRNA levels and activation of apoptotic pathways by Western blotting. In vitro effects of TAT-NBD were determined in a neuronal cell line., Results: Inhibition of cerebral NF-kappaB activity by TAT-NBD had a significant neuroprotective effect; brain damage was reduced by more than 80% with a therapeutic window of at least 6 hours. In contrast to earlier suggestions, the protective effect of TAT-NBD did not involve suppression of early cytokine upregulation after HI. Moreover, NF-kappaB inhibition prevented HI-induced upregulation and nuclear as well as mitochondrial accumulation of p53, prevented mitochondrial cytochrome-c release and activation of caspase-3. Finally, TAT-NBD could directly increase neuronal survival because TAT-NBD was sufficient to inhibit death in a neuronal cell line. A nonactive mutant peptide did not have any effect., Conclusions: Inhibition of NF-kappaB has strong neuroprotective effects that involve downregulation of apoptotic molecules but are independent of inhibition of cytokine production.

It has been suggested that dysregulation of immune-to-brain communication plays a role in the biopsychological process underlying medically unexplained symptoms (MUS). Immune and non-immune stressors can both be involved in the activation of the central sickness-behavioural-system leading to complaints like malaise, pain and fatigue. We hypothesized increased pro-inflammatory and/or reduced anti-inflammatory cytokine activity to exist in MUS patients. Twenty-seven participants (4 male; 23 female) with heterogeneous MUS were compared with 27 healthy controls (6 male; 21 females). Blood samples were analysed for leukocyte subset cell counts, in vitro T-cell mitogen-stimulated cytokine production (IL-2, IL-4, IL-5, IL-6, IL-10, TNF-alpha and IFN-gamma) and in vitro monocyte cytokine release (IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha) in response to increasing concentrations of LPS. No significant group differences were found for any of the cytokines measured. One unexpected exception was an elevation in the number of circulating B and NK-cells in participants high on MUS. Nonetheless, no support was found for the hypothesized immunological dysregulation in peripheral blood leukocyte function of MUS patients.

In the adolescent population, fatigue is associated with somatic complaints, unrefreshing sleep, cognitive disturbances and symptoms of depression and anxiety. This pattern of symptoms resembles the one described in chronic fatigue syndrome (CFS). Since immunological alterations have been reported in CFS patients, we wondered whether also severely fatigued girls from a healthy population would show comparable alterations in psychological and immunological parameters. We tested this hypothesis in a longitudinal design, allowing a reliable assessment of the participants' characteristic immune status. Groups of severely fatigued (N=67) and non-fatigued (N=61) participants were selected. Severely fatigued girls reported more depressive symptoms, anxiety, reduced sleep quality, and somatic and CFS-related symptoms than non-fatigued participants across three measurements during one year (T1: spring, T2: autumn, T3: spring). In contrast, no group differences in mitogen-induced cytokine production or T-cell proliferation in vitro or in leukocyte subset counts were observed. Although absolute cytokine production and cell counts were affected by seasonal variation, the within-subject values, relatively to the rest of the participants, were fairly stable. Data from a small group of CFS patients (N=11) showed similarities in self-reported complaints between CFS patients and fatigued participants. Interestingly, CFS patients showed a distinct immune profile when compared to the severely fatigued or non-fatigued participants, i.e. increased levels of anti-inflammatory cytokines (IL-10, decreased IFN-gamma/IL-10 ratio) and reduced levels of pro-inflammatory cytokines (IL-6, TNF-alpha) over all three time points analyzed. These results show that, although overlap in symptomatology between the general population and patients with CFS was observed, only CFS patients show a skewing of the cytokine balance towards an anti-inflammatory profile.

Objective: To investigate whether or not peri/intraventricular hemorrhages (PIVHs) occurring in the first 12 hours of life (early PIVHs) are related to respiratory distress syndrome (RDS)-associated inflammatory factors in contrast to PIVHs developing after 12 hours of life (late PIVHs)., Study Design: Blood samples obtained at 0 to 12 hours, 48 to 72 hours, and 168 hours of life were evaluated for determination of the proinflammatory cytokines interleukin (IL)-8 and IL-6, tumor necrosis factor (TNF)-alpha, and malondialdehyde (MDA) as measures of lipid peroxidation. Simultaneously, cranial ultrasonography was performed in 114 neonates under 32 weeks gestational age., Results: Out of the total study group of 114 neonates, 67 (59%) had RDS. Early PIVH occurred in 16 neonates, 14 of whom (88%) had RDS. Late PIVHs occurred in 12 neonates. Neonates with RDS had higher IL-8 and IL-6 levels at 0 to 12 hours (P < .0001; < .0001) and at 48 to 72 hours (P < .001; < .01) than those without RDS. Neonates with early PIVH had higher IL-8 (P < .02), IL-6 (P < .02), and MDA (P < .01) levels at 0 to 12 hours than those with late PIVH or no PIVH. Those with early PIVH had higher IL-8 levels at 48 to 72 hours than those without PIVH (P < .02). Multiple linear regression revealed an association between RDS/early PIVH and IL-8, IL-6, and MDA levels., Conclusions: An RDS-associated increase in proinflammatory cytokine and MDA levels was associated with early PIVHs, but not with late PIVHs, suggesting a different etiopathogenesis in early versus late PIVHs.

Objective: To investigate whether oral administration of mycobacterial heat-shock protein 65 (HSP65) during adjuvant arthritis (AA) induces regulatory cells and cytokines., Methods: AA was induced in Lewis rats and from the time of disease onset HSP65 in the presence of soya bean trypsin inhibitor (STI) was administered orally every other day. The number of splenic CD4+CD25+ T cells and antigen-induced cytokine mRNA expression were determined., Results: Oral treatment with HSP65/STI reduced AA symptoms. After one feeding of HSP65/STI, the number of CD4+CD25+ splenic T cells increased and HSP65-specific T cells expressed increased levels of interferon gamma and interleukin 10. After two feedings, the expression of interleukin-10 mRNA remained increased, whereas there was low expression of interferon gamma mRNA. The number of CD4+CD25+ splenic T cells remained increased., Conclusions: Oral treatment with HSP65/STI after AA onset reduces disease symptoms via dynamic changes in the number of CD4+CD25+ splenocytes and in antigen-induced cytokine production.

The family of adrenergic receptors (AR) plays a central role in regulation of the activity of many organ systems. Consequently, regulated expression of the various subtypes of AR is an important mechanism in maintaining homeostasis. Previously, we have shown that alpha(1)-AR triggering of peripheral blood mononuclear cells from patients with juvenile chronic arthritis results in increased IL-6 production. In contrast, alpha(1)-AR agonists do not alter cytokine production by cells of healthy individuals. The aim of the present study was to investigate whether pro-inflammatory cytokines can regulate the expression of mRNA encoding AR of the alpha(1)-family. We show that human THP-1 monocytic cells express mRNA encoding of two of the three cloned subtypes of alpha(1)-AR: alpha(1b)-AR and alpha(1d)-AR mRNA. The cytokines TNF-alpha and IL-1beta decrease level of mRNA for alpha(1d)-AR in THP-1 monocytic cells. In contrast, alpha(1b)-AR mRNA levels are not affected by these two cytokines. Interestingly, IL-1beta and TNF-alpha induce the expression of alpha(1a)-AR mRNA in THP-1 monocytic cells. In human umbilical vein endothelial cells (HUVEC), IL-1beta and TNF-alpha decrease both alpha(1b)-AR and alpha(1d)-AR mRNA levels in HUVEC. alpha(1a)-AR mRNA is not detectable in HUVEC.IL-6 and IL-8, two other pro-inflammatory cytokines tested in this study, do not change alpha(1)-AR subtype levels in HUVEC or monocytic cells. Our data demonstrate that TNF-alpha and IL-1beta can regulate expression of alpha(1)-AR mRNA and that cytokine regulation of alpha(1)-AR expression is subtype- and tissue-specific.

Objective: This study was undertaken to examine the hypothesis that mechanical ventilation in association with anesthesia would alter the cytokine profile in infants without preexisting lung pathology., Design and Setting: Prospective observational study in pediatric intensive care unit in a university hospital., Patients: Twelve infants who were subjected to an uncomplicated diagnostic cardiac catheterization procedure were studied. All subjects were ventilated with a volume control mode, 0.3 FIO(2), 4 cmH(2)O PEEP, and 10 ml/kg tidal volume. Volatile (servoflurane) anesthetics were given., Measurements and Results: Tracheal aspirates and blood samples were obtained before and after 2 h of mechanical ventilation. In tracheal aspirates and in supernatants of stimulated whole-blood cultures cytokine concentrations were measured. In the tracheal aspirates the immune balance was characterized by a proinflammatory response pattern, with a significant increase in TNF-alpha and IL-6 concentrations; concentrations of anti-inflammatory mediators remained very low. The functional capacity of peripheral blood leukocytes to produce INF-gamma, TNF-alpha, and IL-6 in vitro was significantly decreased. This was accompanied by a significant decrease in the killing activity of natural killer cells., Conclusions: Two hours of servoflurane and mechanical ventilation using a tidal volume of 10 ml/kg is associated with remarkable changes in the immune response in infants without preexisting lung pathology undergoing cardiac catheterization. In the lungs the immune balance favors a proinflammatory response pattern without detectable concentrations of anti-inflammatory mediators. The Th1 immune response by peripheral blood leukocytes was decreased. The observed change in Th1/Th2 balance in favor of Th2 cytokine activity may be a systemic adaptation to the proinflammatory milieu in the lung.

Objective: To study whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) differ from healthy individuals in their immune responses to acute psychological stress., Methods: The phenotype and function of peripheral blood lymphocytes were analysed before and after stress exposure in patients and healthy subjects., Results: Natural killer (NK) cell numbers increased transiently in all groups under stress. NK activity, however, increased in healthy controls only. We observed a stress-induced increase in interleukin (IL)-4-producing (IL-4(+)) cells in SLE patients only, whereas interferon (IFN) gamma(+) cell numbers increased due to stress in all three groups. An analysis of supernatants from phytohaemagglutinin (PHA) cultures revealed increased IFN gamma and IL-10 levels in healthy subjects but not in SLE or RA patients after stress exposure., Conclusions: These data demonstrate that RA and SLE patients differ in their immune response to stress from healthy controls. Changes in cytokine patterns might be responsible for stress-induced exacerbation of disease activity in RA and SLE patients.

Unlabelled: The systemic inflammatory response that occurs after cardiopulmonary bypass shows many changes similar to those seen in sepsis. The mechanisms for these changes have been attributed to cellular and humoral activation, such as increased secretion of cytokines and complement. The aim of our study was to investigate the cytokine pattern of pro- and anti-inflammatory cytokines in young children during and after bypass surgery. Nineteen children undergoing either septal defect correction (n = 12), or more complex surgery (n = 7), were prospectively included in this study. There were significant higher pre-operative levels of circulating cytokines in the latter group. Cardiopulmonary bypass surgery induced in both groups a rise in circulating cytokine levels and a sharp decline in the capacity of the leucocytes to secrete interleukines-6 and -8 in response to ex vivo stimulation with lipopolysaccharide. Ex vivo production of interleukine-1 receptor antagonist was slightly attenuated by the procedure., Conclusions: The downregulation of ex vivo pro- and, to some extent, anti-inflammatory cytokine production may be a reflection of a cellular stress response, induced by anaesthesia, cardiopulmonary bypass and surgery.

Variability in susceptibility to diseases is a well known phenomenon that has been attributed to genetic and environmental factors. At the level of the immune system, the reactivity of two types of T helper cells (Th1 and Th2 cells) plays an important role in determining disease susceptibility. Inflammatory (autoimmune) diseases are stimulated by cytokines produced by Th1 cells. Th2 cytokines stimulate antibody production (e.g., IgE) and eosinophilia as observed in allergic reactions or during parasitic infections. We describe here that the reactivity in a Th1 or a Th2 disease model significantly differs between individual rats that show group-specific differences in reactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as well as in their behavioral responses to stress. We used two outbred lines of Wistar rats, apomorphine-susceptible rats that have a relatively hyperreactive HPA axis (APO-SUS) and apomorphine-unsusceptible rats that have a relatively hyporeactive HPA axis (APO-UNSUS). APO-SUS, but not APO-UNSUS, rats generated a vigorous, Th2-dependent IgE response after infection with the nematode Trichinella spiralis. In contrast, APO-UNSUS, but not APO-SUS, rats were susceptible for Th1-mediated experimental autoimmune encephalomyelitis. Investigation of cytokine responses of splenocytes revealed that the ratio of mRNA expression for Th1-derived interferon (IFN)-gamma and mRNA expression of Th2-derived interleukin-4 (IL-4) was significantly smaller in APO-SUS than in APO-UNSUS rats. In conclusion, individual differences in structure and reactivity of the neuroendocrine system co-occur with group-specific differences in susceptibility to inflammatory and infectious diseases.