Proinflammatory Cytokines In Blood Research Articles

Cardiovascular system diseases in patients with polycystic ovary syndrome – the role of inflammation process in this pathology and possibility of early diagnosis and prevention

Polycystic ovary syndrome is a disorder which affects 5-10% of women in reproductive age. PCOS is a cause of hyperandrogenism, menstrual disorders and infertility. The most common clinical symptoms are hirsutism, acne and obesity. Patients often suffer from metabolic disorders: insulin resistance, hyperinsulinemia, dislipidemia, leading to atherosclerosis and others irregularities of the metabolic syndrome. Patients are in the high risk group for cardiovascular diseases (CVD) development because of the metabolic abnormalities. Obesity is observed in 35-60% of women with PCOS. Lean women with PCOS are also exposed to a greater risk of glucose intolerance development and abnormalities in lipid profile than women without PCOS with comparable BMI. Adipocytes are the source of many compounds of the paracrine and endocrine activity. Some of them are also markers and mediators of inflammation. Increased levels of proinflammatory cytokines in blood can promote atherosclerosis and cardiovascular disease. Markers: IL-18, TNF, IL-6 and hs-CRP are often elevated in patients with polycystic ovary syndrome. An increase in inflammatory markers may be an early indicator of the risk of developing insulin resistance and atherosclerosis, and may become a useful prognostic and therapeutic tool for monitoring patients with PCOS: lean and those with overweight and obesity. Assessment of the concentrations of inflammatory markers may become a very useful test in evaluating the risk of developing atherosclerosis and cardiovascular disease, long before their clinical manifestation. It will also allow for the appropriate prophylaxis.

Anaemia in patients with HIV-associated TB: relative contributions of anaemia of chronic disease and iron deficiency.

SUMMARYBACKGROUND: Anaemia commonly complicates both human immunodeficiency virus (HIV) infection and tuberculosis (TB), contributing substantially to morbidity and mortality. The mechanisms underlying anaemia and corresponding treatments in co-infected patients are poorly defined.OBJECTIVE: To determine the relative contributions of anaemia of chronic disease (ACD) and iron deficiency to anaemia in patients with HIV-associated TB.DESIGN: Consecutively recruited hospitalised (n = 102) and matched ambulatory patients (n = 51) with microbiologically confirmed HIV-associated TB in Cape Town, South Africa, were included. Haemoglobin levels, iron status markers, hepcidin and pro-inflammatory cytokines in blood were measured. We determined the prevalence of ACD and iron-deficiency anaemia (IDA) using seven different published definitions of IDA.RESULTS: More than 80% of enrolled HIV-associated TB patients were anaemic, and anaemia was more severe among in-patients. Over 95% of anaemic HIV-associated TB patients had ACD, whereas the proportion with IDA using a range of seven different definitions was low overall (median < 3%, range 0–32.6) in both patient groups. The proportion with IDA and hepcidin concentration ⩽ 20.0 ng/ml (predictive of responsiveness to oral iron supplementation) was also very low (median < 3%, range 0–15.1).CONCLUSIONS: ACD was the predominant cause underlying anaemia in HIV-associated TB patients, and IDA was very uncommon in this setting. The majority of anaemic HIV-associated TB patients were unlikely to benefit from oral iron supplementation.

Distinct cytokine/chemokine network in semen and blood characterize different stages of HIV infection.

The cytokine/chemokine network is used by the innate and adaptive immune system to orchestrate effective immune responses. Here, we describe the cross-sectional association between cytokine levels and stage of HIV infection to gain novel insights into HIV-1 immunopathogenesis and identify novel therapeutic targets. Concentrations of 31 cytokine/chemokines were retrospectively measured in blood and seminal plasma collected from 252 individuals enrolled in four well characterized cohorts: HIV-uninfected, untreated HIV-infected in early phase of infection, untreated HIV-infected in late phase of infection, and HIV-infected on antiretroviral therapy with undetectable HIV RNA levels in blood (<50 copies/ml). Cytokine/chemokine levels were measured by multiplex-bead array. Comparisons between groups were performed by Mann-Whitney U-test and P values were adjusted for multiple comparisons using the Benjamini-Hochberg method. Presence of HIV-infection skewed the cytokine/chemokine network towards a pro-inflammatory response in both blood and semen compared to HIV-uninfected controls. Such changes emerged within the first weeks of infection and were maintained thereafter: Among untreated HIV-infected individuals, none of the 31 measured cytokines were significantly different between early and later stages of infection. Suppression of plasma HIV RNA with ART did not result in normalization of the levels of pro-inflammatory cytokines in blood. In semen, several pro-inflammatory cytokines were even further upregulated in ART-treated compared with HIV-uninfected and HIV-untreated individuals. A profound disruption in the cytokine/chemokine network is evident in blood and semen from the earliest stage of HIV infection shortly after the first detection of systemic viremia. These changes are maintained throughout the chronic phase of the infection and do not normalize despite ART and suppression of plasma HIV RNA.

Peculiarities of coagulation hemostasis disorders in patients with chronic obstructive pulmonary disease.

.The violation of blood coagulation properties is observed in many diseases of the respiratory system, including chronic obstructive pulmonary disease (COPD). It is known that in a stable COPD phase release of proinflammatory cytokines in blood is observed, it leads to disturbance of hemostasis parameters toward hypercoagulation. The aim of our study was to determine possibility of coagulation disorders formation in patients with COPD in a stable phase of pathological process at different stages of disease course and identify relationship between coagulation parameters levels and degree of violation of ventilation lung function. Materials and methods. We examined 30 patients with COPD in a stable disease phase, included in the main group (FEV1 =49,5±15,5% of the due, there were 27 men (90.0%), 3 (30.0%) women, mean age was 61,8±7,9 years, level of pack /years index - 34,2±15,3). The control group consisted of 10 healthy subjects matched with the patients of the main group by age and sex. All patients were divided into 2 subgroups. Subgroup 1 included 16 patients with moderate COPD, that is the level of FEV1&gt;50% (61,8±7,4% of predicted), and subgroup 2 - 14 COPD patients with severe COPD, that is the level of FEV1 &lt;50% (35,3±8,2% of predicted). Patients received standard treatment according to the disease stage. Main indicators of coagulation levels: prothrombin index (PI), prothrombin ratio (PR), international normalized ratio (INR), activated partial thromboplastin time (APTT), thrombin time (TT) and antithrombin III (AT III) were identified in all patients. Results. The levels of PI, PR and INR in the subgroup 1 differed significantly from those of in the subgroup 2, control group (p&lt;0,05) and pointed at hypercoagulation, whereas in the subgroup 2 all indicators were absolutely identical with control group. Correlation link between the level of INR levels and FEV1 (r=-0,73; p&lt;0.01) in patients of the main group was determined. Levels of APTT, TT and AT III in the main group and in subgroups 1 and 2 were identical to those of the control group. There were no significant differences of these parameters between subgroups 1 and 2. Conclusions. In patients with COPD already at early stage of the disease abnormalities of coagulation hemostasis link mainly on external coagulation pathway toward hypercoagulation develop.

Differential effects of platelets and platelet inhibition by ticagrelor on TLR2- and TLR4-mediated inflammatory responses.

Platelets and platelet-monocyte interaction play an important role in inflammation. Both pro- and anti-inflammatory effects of platelet inhibition have been reported in animal models. This study aimed to investigate the effect of platelets and platelet inhibition by the new P2Y12 receptor antagonist ticagrelor on monocyte function, as assessed by cytokine responses to Toll-like Receptor (TLR) ligands. In a set of in vitro experiments, peripheral blood mononuclear cells (PBMC) incubated with the TLR2 ligand Pam3CSK4 produced less cytokines in the presence of platelets, whereas platelets increased the production of cytokines when PBMC were exposed to TLR4 ligand lipopolysaccharide (LPS). These effects of platelets were dependent on direct platelet-leukocyte aggregation and for the Pam3CSK4-induced response, on phagocytosis of platelets by monocytes. In a double blind, placebo-controlled crossover trial in healthy volunteers, a single oral dosage of 180 mg ticagrelor reduced platelet-monocyte complex (PMC) formation. This was associated with an increase in pro-inflammatory cytokines in blood exposed to Pam3CSK4, but a decrease in these cytokines in blood exposed to LPS. These findings show that platelets differentially modulate TLR2- and TLR4-mediated cytokine responses of PBMC. Through inhibition of platelet-leukocyte interaction, P2Y12 receptor antagonists may either exert a pro- or anti-inflammatory effect during infections depending on the TLR primarily involved.

Dexmedetomidine premedication attenuates concanavalin A-induced hepatitis in mice

Activated T cells selectively induced by concanavalin A (Con A) in liver are subsequent efficient resolution of inflammation. Activated T cells infiltrating in liver combined with pro-inflammatory cytokines are the major causes in Con A-induced liver injury. In our study, C57/BL mice were injected with Con A combined with dexmedetomidine or not. ALT and AST in blood and histopathology of liver were measured. T cell infiltration in liver was examined by flow cytometry and pro-inflammatory cytokines including IL-6, IL-10, TNF-α, and IFN-γ in blood were measured by ELISA. The mRNA level of CXCL10 was detected by RT-PCR and the protein level of NF-κB was measured by Western-blot. We found that dexmedetomidine alleviated Con A-induced liver injury by down-regulating levels of ALT and AST in blood and the severity of histopathology, which reflect the severity of hepatitis induced by Con A. In addition, pro-inflammatory cytokines in blood were attenuated by dexmedetomidine. Dexmedetomidine restrained the phosphorylation of NF-κB IκBα and P-65 dramatically which may participate in the regulation of cytokines secretion. Moreover, CXCL10 mRNA attenuated by dexmedetomidine in liver may result in the lower level of CD4(+) T cells infiltration in liver. These results suggested that dexmedetomidine might be a potential compound in treating T cell-mediated liver injury.

Relationship between the induction of inflammatory processes and infectious diseases in patients with ischemic stroke.

Pro-inflammatory cytokines participate in the induction of ischemic stroke. So far, their participation in the cerebral ischemia was proven for the tumor necrosis factor TNF-α, interleukin-1 (IL-1), and interleukin-6 (IL-6). The release of the pro-inflammatory cytokines into the extracellular space causes the enlargement of the brain damage region, and consequently increases the neurological deficit and negatively affects the survival rate prognoses. That is confirmed by the increased concentration of pro-inflammatory cytokines in blood and the cerebrospinal fluid of patients with brain stroke, as well as by the research on the induced/experimental cerebral ischemia in animals. The pro-inflammatory cytokines participate in the migration of the reactive T lymphocytes to the regions of brain ischemia where they enhance the nerve tissue damage by down-regulation of microcirculation, induce the pro-thrombotic processes and release other neurotoxic cytokines. Also, in the early stage of cerebral ischemia, cytokines activate the axis hypothalamus-pituitary gland-adrenal cortex and increase the cortisol concentration in blood, what results in the decreased resistance to infectious diseases. Administration of the inhibitor of the interleukin-1 receptor (IL-1Ra) inhibits the inflammatory processes in the region of brain ischemia, and subsequently improves the prognosis for the size of the neurological deficit and the survival rate, as well as resistance to infectious diseases.

Профіль прозапальних цитокінів при цукровому діабеті 1-го типу

The study involved 70 patients with type 1 diabetes who were under medical care in the clinical city hospital. Patients were divided into two groups: group I included patients with severe form of diabetes with complications and group II included patients without complications. The cytokine profile in the diabetes mellitus patients was investigated. The study showed that all indices of proinflammatory cytokines in patients of both groups were higher than in control healthy subjects. The positive correlation between the level of proinflammatory cytokines in blood and severity of the course of disease was revealed.

Na+/K+-ATPase dependent regulation of astrocyte Ca2+ signalling: A novel mechanism for modulation of long-term pain?

Abstract Background Long-term or chronic pain represents a major health problem and is associated with significant socio-economic costs. During injury, pain can be dissociated from its normal physiological role. It can persist for a longer period of time, even after the primary noxious stimulus has more or less subsided. Analgesic drugs, with predominant neuronal sites of actions, seem to be relatively ineffective. Chronic pain is probably partly a consequence of ongoing neuroinflammation. The mechanisms behind these phenomena, and how the neuronal and non-neuronal activities evoked by painful stimuli and inflammation are processed in the brain and throughout the CNS, are not well understood. Methods Primary cultures, calcium imaging, immunocyto-chemistry, Western blotting, cytokine release. Results Following pain stimuli increased activity of inflammatory receptors and shifts in intra- and extracellular ion concentrations occur within the CNS. One signalling pathway in astrocytes propagates Ca2+ waves, which initially decrease and then increase in form of oscillations in the astrocyte networks. This causes dysfunction in the astrocytic Ca2+ signalling resulting in down-regulation of Na+ transporters, and increased release of pro-inflammatory cytokines. The neurons will then increase their excitability and, hypothetically, also increase the sensitivity for development or potentiation of neuropathic pain states. Low-dose of potential anti-inflammatory and analgesic drugs restore the disturbed astrocytic Ca2+ signalling, and modulate the activity of inflammatory receptors and Na+/K+-ATPase. We recently report, in patients with long-term pain, changes in neurotrophic factors and pro-inflammatory cytokines in blood and CSF. Conclusions Dysfunction in downregulation of Na+ transporters, changed Ca2+ signalling in the astrocyte networks and release of cytokines from glial cells can lead to pathogenic chronic neuroinflammation. Modulation of the Na+/K+-ATPase activity and restoration with anti-inflammatory substances will lead to a balance between inflammatory and anti-inflammatory mediators in inflammatory reactive cells. The pharmacological treatment of today is directed towards neuronal over-excitability, unfortunately with less success. A novel pharmacological treatment strategy would thus be directed towards the activated astrocytes and microglial cells, being the source of the neuroinflammation. This will be an important knowledge for treatment in clinical therapy.

Prophylactic Application of CpG Oligonucleotides Augments the Early Host Response and Confers Protection in Acute Melioidosis

Prophylactic administration of CpG oligodeoxynucleotides (CpG ODNs) is known to confer protection against lethal sepsis caused by Burkholderia pseudomallei in the mouse model. The mechanisms whereby CpG regulates the innate immune response to provide protection against B. pseudomallei, however, are poorly characterized. In the present study, we demonstrate that intranasal treatment of mice with Class C CpG, results in recruitment of inflammatory monocytes and neutrophils to the lung at 48 h post-treatment. Mice infected with B. pseudomallei 48 h post-CpG treatment had reduced organ bacterial load and significantly altered cytokine and chemokine profiles concomitant with protection as compared to control animals. CpG administration reduced the robust production of chemokines and pro-inflammatory cytokines in blood, lung and spleen, observed following infection of non-treated animals. Death of control animals coincided with the time of peak cytokine production (day 1–3), while a moderate; sustained cytokine production in CpG-treated animals was associated with survival. In general, CpG treatment resulted in diminished expression of cytokines and chemokines post-infection, though IL-12p40 was released in larger quantities in CpG treated animals. In contrast to CpG-treated animals, the lungs of infected control animals were infiltrated with leukocytes, especially neutrophils, and large numbers of necrotic lesions were observed in lung sections. Therapeutic treatment of B. pseudomallei-infected animals with CpG at 24 h post-infection did not impact survival compared to control animals. In summary, protection of CpG-treated animals was associated with recruitment of inflammatory monocytes and neutrophils into the lungs prior to infection. These responses correspond with early control of bacterial growth, a dampened inflammatory cytokine/chemokine response, reduced lung pathology, and greatly increased survival. In contrast, a delay in recruitment of inflammatory cell populations, despite a robust production of pro-inflammatory cytokines, was associated with poorly controlled bacterial growth, severe lung pathology, and death of control animals.

Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells

Natalizumab is an antibody directed against integrin alpha4 that reduces disease activity in patients with multiple sclerosis (MS) by blocking migration of T and B cells into the CNS. The goal of this study was to characterize the effects of natalizumab treatment on cytokine production and expression of activation markers, costimulatory molecules, and trafficking determinants on CD4+ and CD8+ T cells. In a longitudinal study, we investigated the expression of surface makers and cytokine expression on peripheral blood lymphocytes from 28 patients with MS who started natalizumab treatment and were followed for 1 year. A mixed effects model was used to compare pretreatment to on-treatment measurements. The frequency of CD4+ T cells producing interferon-gamma, tumor necrosis factor, and interleukin (IL)-17 upon anti-CD3 stimulation increased 6 months after initiation of natalizumab treatment and remained elevated throughout the follow-up. The frequency of CD4+ T cells expressing CD25, HLA-DR, and CCR6 ex vivo was increased at one or more time points during treatment. Among CD8+ T cells, the frequency of cells producing IL-2 and IL-17 after stimulation was increased during natalizumab treatment, as was the frequency of CD8+ T cells expressing CD58 and CCR5 ex vivo. The increase in the frequency of activated cells could not be replicated by in vitro exposure to natalizumab. Natalizumab treatment increases the percentage of activated leukocytes producing proinflammatory cytokines in blood, presumably due to sequestration of activated cells in the peripheral circulation.

Endoplasmic Reticulum Stress: Another Link Between Obesity and Insulin Resistance/Inflammation?

Obesity, which has reached epidemic proportions in the U.S. and is increasing worldwide, is closely associated with insulin resistance (peripheral and hepatic) and with a state of low-grade inflammation, the latter characterized by elevated levels of proinflammatory cytokines in blood and tissues (1). Insulin resistance and inflammation in turn are associated with type 2 diabetes, hypertension, atherogenic dyslipidemias, and disorders of blood coagulation and fibrinolysis, all of which are independent risk factors for the development of atherosclerotic vascular disease, including heart attacks, strokes, and peripheral arterial disease (1). The reason why obesity is so closely associated with insulin resistance and inflammation is not completely understood. On one hand, there is evidence to show that blood levels of free fatty acids (FFAs) play an important role in the development of obesity-related insulin resistance and inflammation (rev. in 2). Plasma FFA levels are increased in most obese people, and acutely raising plasma FFA levels increases insulin resistance as well as the expression of proinflammatory cytokines, whereas lowering plasma FFA levels reduces insulin resistance. Mechanisms involved in FFA-induced insulin resistance include accumulation (in muscle and liver) of lipids and lipid intermediates such as diacylglycerol, activation of several protein kinase C isoforms, reduction in tyrosine phosphorylation of the insulin receptor substrates 1 and 2 (2), and activation of the proinflammatory nuclear factor-κB pathway (3,4). On the other hand, not all obese insulin-resistant subjects have elevated plasma …

Increased intracellular T helper 1 proinflammatory cytokine production in peripheral blood, bronchoalveolar lavage and intraepithelial T cells of COPD subjects

The role of T cells in the pathophysiology of chronic obstructive pulmonary disease (COPD) is not yet certain, although varying reports have shown increases in T helper 1 (Th1) and/or Th2 cytokines in peripheral blood and bronchoalveolar lavage (BAL). No studies have examined cytokine production by intraepithelial T cells obtained by bronchial brushing (BB). Intracellular cytokine analysis of T cell subsets from peripheral blood, BAL and BB from smoker and ex-smoker COPD patients, COPD patients receiving inhaled corticosteroids and smoker and non-smoker control subjects was studied using multi-parameter flow cytometry. CD4 : CD8 inversion was noted in the peripheral blood of smoker and ex-smoker COPD groups, in BAL and BB from smoker controls and BAL of COPD smokers. There was an increase in intracellular CD8(+) T cell Th1 proinflammatory cytokines in some COPD groups in the peripheral blood and in CD8(+) T cell tumour necrosis factor (TNF)-alpha in some COPD groups and smoker controls in BAL and BB. There was an increase in proinflammatory cytokines in COPD smokers compared with ex-smokers and a decrease in COPD smokers receiving inhaled corticosteroids in the airways. There was a negative correlation between forced expiratory volume in 1 s (FEV(1)) and the percentage of BAL and intraepithelial CD8(+) T cells producing TNF-alpha. COPD patients exhibit systemic inflammation as evidenced by increased intracellular Th1 proinflammatory cytokines in blood, BAL and intraepithelial CD8(+) T cells, whereas smoker controls showed localized Th1 response in the lung only. Systemic therapeutic targeting of TNF-alpha production by CD8(+) T cells may improve morbidity in COPD patients while targeting of TNF-alpha in the lung may prevent smokers progressing to COPD.

Increase in transforming growth factor-β in the brain during infection is related to fever, not depression of spontaneous motor activity

When viral infection occurs, this information is transmitted to the brain, and symptoms such as fever and tiredness are induced. One of the causes of these symptoms is the secretion of proinflammatory cytokines in blood and the brain. In this study, the i.p. administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA, to rats was used as an infection model. Poly I:C decreased spontaneous motor activity (SMA) 2 h after i.p. administration, and this decrease was maintained thereafter. The concentration of active transforming growth factor-β (TGF-β) in cerebrospinal fluid (CSF) increased 1 h after the administration. This increase occurred earlier than those in the concentrations of other proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), in serum. The intracisternal administration of an anti-TGF-β antibody partially inhibited fever induced by poly I:C administration; however, this treatment did not affect the decrease in SMA. Furthermore, intracisternal administration of TGF-β raised the body temperature. These results indicate that TGF-β in the brain, which was increased by poly I:C administration, is associated with fever but not with a decrease in SMA.

Preoperative optimization of the high-risk surgical patient

Intra-abdominal, thoraco-abdominal and vascular surgery is associated with a significant incidence of postoperative complications and mortality. Major surgery of body cavities produces a strong inflammatory response, which in turn causes a marked increase in oxygen requirement. Subjects who have a stronger inflammatory response (as judged by concentrations of pro-inflammatory cytokines in blood) are more likely to develop complications. To survive major surgery, the patient must have an adequate cardiorespiratory reserve to raise cardiac output and oxygen delivery to meet the increase in oxygen demand. The high-risk patient cannot spontaneously raise his cardiac output to the required level, leading to inadequate perfusion of tissue, multi-organ dysfunction, multi-organ failure and possibly death. High-risk patients can be identified (if time permits) by dynamic functional assessment of cardiorespiratory function. Appropriate therapy (e.g. beta-blockers, statins) should be started to optimize physical condition before surgery. Perioperative treatment strategies aimed at improving these abnormalities in tissue perfusion, using carefully monitored physiological variables, are termed ‘goal-directed therapies’; they reduce postoperative morbidity and mortality, particularly in high-risk patients with pre-existing cardiorespiratory disease. Perioperative haemodynamic optimization requires additional monitoring, resources and environment (ICU or HDU), but significantly improves outcome in the patients at most risk.

Melanocortin peptides inhibit production of proinflammatory cytokines in blood of HIV-infected patients

Melanocortins are proopiomelanocortin-derived peptides that include adrenocorticotropic hormone [ACTH (1–39)], α-melanocyte-stimulating hormone [α-MSH (1–13)], and related amino acid sequences. Melanocortin peptides have potent antiinflammatory/anticytokine activity. Because cytokines such as interleukin 1 (IL-1) and tumor necrosis factor (TNF) can be detrimental in HIV-infected patients, we investigated the effects of melanocortins on production of IL-1 and TNF α in the blood of HIV patients. Cytokine production was measured in whole blood samples stimulated with LPS in the presence or absence of α-MSH (1–13), α-MSH (11–13), ACTH (1–24), or ACTH (1–39). Melanocortins reduced production of both cytokines in a concentration-dependent fashion. In separate experiments on normal peripheral blood mononuclear cells (PBMC), α-MSH (1–13) inhibited production of IL-1 β and TNF α induced by HIV envelope glycoprotein gp 120. These results suggest that stimulation of melanocortin receptors in inflammatory cells could be a novel way to reduce production of cytokines that promote HIV replication.