Role Of Proinflammatory Cytokines Research Articles

Current mechanisms in obesity and tumor progression.

Hyperadiposity, as present in obesity, is a substantial threat to cancer risk and prognosis. Studies that have investigated the link between obesity and tumor progression have proposed several mechanistic frameworks, yet, these mechanisms are not fully defined. Further, a comprehensive understanding of how these various mechanisms may interact to create a dynamic disease state is lacking in the current literature. Recent work has begun to explore not only discrete mechanisms by which obesity may promote tumor growth (for instance, metabolic and growth factor functions of insulin; inflammatory cytokines; adipokines; and others), but also how these putative tumor-promoting factors may interact. This review will highlight the present understanding of obesity, as it relates to tumor development and progression. First, we will introduce the impact of obesity in cancer within the dynamic tumor microenvironment, which will serve as a theme to frame this review. The core of this review will discuss recently proposed mechanisms that implicate obesity in tumor progression, including chronic inflammation and the role of pro-inflammatory cytokines, adipokines, hormones, and genetic approaches. Furthermore, we intend to offer current insight in targeting adipose tissue during the development of cancer prevention and treatment strategies.

Aseptic Μeningitis in Hereditary Autoinflammatory Diseases

Autoinflammatory diseases (ADs) refer to a group of disorders of the innate immune system, mainly monogenic, marked by episodes of systemic inflammation. Aseptic meningitis is a rare neurological manifestation of ADs characterized by meningeal inflammation, negative routine cultures in the cerebrospinal fluid and identical signs and symptoms of bacterial meningitis. Herein, the aim of this review article is to describe the association between aseptic meningitis and ADs, especially in patients with familial Mediterranean fever (FMF) and chronic infantile neurological cutaneous articular (CINCA) syndrome. We will discuss the emerging role of proinflammatory cytokines, such as interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in the pathogenesis of aseptic meningitis in ADs, and will explore recent treatment developments, such as the use of biological agents.

A Specific Inflammatory Profile Underlying Suicide Risk? Systematic Review of the Main Literature Findings.

Consistent evidence indicates the association between inflammatory markers and suicidal behavior. The burden related to immunological differences have been widely documented in both major affective disorders and suicidal behavior. Importantly, abnormally elevated pro-inflammatory cytokines levels have been reported to correlate with suicidal behavior but whether and to what extent specific inflammatory cytokines abnormalities may contribute to our understanding of the complex pathophysiology of suicide is unknown. The present manuscript aimed to systematically review the current literature about the role of pro-inflammatory cytokines in suicidal behavior. Most studies showed a link between abnormally higher interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), kynurenic acid (KYN), and lower IL-2, IL-4, and interferon (IFN)-γ levels in specific brain regions and suicidal behavior. Unfortunately, most studies are not able to exclude the exact contribution of major depressive disorder (MDD) as a mediator/moderator of the link between inflammatory cytokines abnormalities and suicidal behavior. The association between suicidal patients (both suicide attempters or those with suicidal ideation) and the altered immune system was documented by most studies, but this does not reflect the existence of a specific causal link. Additional studies are needed to clarify the immune pathways underlying suicidal behavior.

The Role of Selected Pro-Inflammatory Cytokines in Pathogenesis of Ischemic Stroke.

Stroke is currently one of the most common causes of death and disability in the world, and its pathophysiology is a complex process, involving the oxidative stress and inflammatory reaction. Unfortunately, no biochemical factors useful in the diagnostics and treatment of stroke have been clearly established to date. Therefore, researchers are increasingly interested in the inflammatory response triggered by cerebral ischemia and its role in the development of cerebral infarction. This article gives an overview of the available literature data concerning the role of pro-inflammatory cytokines in acute stroke. Detailed analysis of their role in cerebral circulation disturbances can also suggest certain immune response regulatory mechanisms aimed to reduce damage to the nervous tissue in the course of stroke.

Pro-inflammatory cytokines in the paraventricular nucleus mediate the adipose afferent reflex in rats.

Our previous study showed that the adipose afferent reflex (AAR) induced by chemical stimulation of white adipose tissue (WAT) increased sympathetic outflow and blood pressure. We also found that pro-inflammatory cytokines (PICs) in the hypothalamic paraventricular nucleus (PVN) potentiate the cardiac sympathetic afferent reflex in rats. However, the role of PICs in the PVN in regulating the AAR is still not clear. This study determined whether PICs in the PVN mediate the AAR in rats. The AAR was evaluated based on renal sympathetic nerve activity and mean arterial blood pressure in response to capsaicin injection into inguinal WAT (iWAT). PIC levels were measured by ELISA. PVN microinjection with the PICs tumor necrosis factor (TNF)-α or interleukin (IL)-1β enhanced the AAR in a dose-dependent manner. Furthermore, pretreatment via the bilateral microinjection of the TNF-α-blocker etanercept or IL-1β blocker IL-1ra into the PVN attenuated the AAR. In rats pretreated with TNF-α or IL-1β, a sub-response dose of angiotensin II (Ang II) significantly enhanced the AAR. Moreover, delivery of the angiotensin II type 1(AT1) receptor antagonist losartan into the PVN attenuated the effects of TNF-α or IL-1β on the AAR. In addition, stimulating either iWAT or retroperitoneal WAT with capsaicin increased TNF-α or IL-1β levels in the PVN, but the injection of capsaicin into the jugular vein, skeletal muscle, and skin had no effects on TNF-α or IL-1β levels in the PVN. These results suggest that TNF-α or IL-1β and Ang II in the PVN synergistically enhance the AAR in rats.

Роль провоспалительных цитокинов в развитии почечной дисфункции

Роль провоспалительных цитокинов в развитии почечной дисфункции

TLR3 agonists induce fibronectin aggregation by activated astrocytes: a role of pro-inflammatory cytokines and fibronectin splice variants

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system which eventually results in axonal loss mainly due to failure of remyelination. Previously we have shown that the persistent presence of stable astrocyte-derived fibronectin aggregates in MS lesions impairs OPC differentiation, and thereby remyelination. Here we set out to discern whether and, if so, how inflammatory mediators as present in MS lesions trigger astrocytes to form fibronectin aggregates. Our findings revealed that in slice cultures only upon demyelination, the TLR3 agonist Poly(I:C) evoked astrocytes to form fibronectin aggregates. Consistently, pro-inflammatory cytokine-pretreated astrocytes were more susceptible to Poly(I:C)-induced fibronectin aggregation, indicating that astrocytes form fibronectin aggregates upon a double hit by inflammatory mediators. The underlying mechanism involves disrupted fibronectin fibrillogenesis at the cell surface as a result of a cytokine-induced increase in relative mRNA levels of EIIIApos-Fn over EIIIBpos-Fn and a Poly(I:C)-mediated decrease in integrin affinity. Remarkably, fibronectin aggregation is exacerbated by white matter astrocytes compared to grey matter astrocytes, which may be a reflection of higher expression levels of EIIIApos-fibronectin in white matter astrocytes. Hence, interfering with alternative fibronectin splicing and/or TLR3-mediated signaling may prevent fibronectin aggregation and overcome remyelination failure in MS lesions.

Role of pro-inflammatory cytokines in the pathogenesis of preterm birth and preeclampsia

Role of pro-inflammatory cytokines in the pathogenesis of preterm birth and preeclampsia

Роль провоспалительных цитокинов в активации латентной внутриклеточной инфекции при аутоиммунных ревматических болезнях и туберкулезе

Роль провоспалительных цитокинов в активации латентной внутриклеточной инфекции при аутоиммунных ревматических болезнях и туберкулезе

Role of Proinflammatory Cytokines in Feedback Modulation of Circadian Clock Gene Rhythms by Saturated Fatty Acids

Proinflammatory signaling cascades have been implicated in the mechanism by which high fat diet (HFD) and saturated fatty acids (SFA) modulate fundamental circadian properties of peripheral clocks. Because the cytokines TNFα and IL-6 are key signals in HFD- and SFA-induced proinflammatory responses that ultimately lead to systemic insulin resistance, the present study examined the roles of these cytokines in the feedback modulation of peripheral circadian clocks by the proinflammatory SFA, palmitate. IL-6 and TNFα secretion in Bmal1-dLuc fibroblast cultures was increased during palmitate treatment although the time course and amplitude of the inductive response differed between these cytokines. Similar to the time-dependent phase shifts observed in response to palmitate, treatment with IL-6 or with the low dose (0.1 ng/ml) of TNFα at hour 12 (i.e., after forskolin synchronization) induced phase advances of fibroblast Bmal1-dLuc rhythms. In complementary experiments, treatment with neutralizing antibodies against these proinflammatory cytokines or their receptors to inhibit of IL-6- or TNFα-mediated signaling repressed palmitate-induced phase shifts of the fibroblast clock. These studies suggest that TNFα, IL-6 and other proinflammatory cytokines may mediate the feedback modulation of peripheral circadian clocks by SFA-induced inflammatory signaling.

Inflammatory biomarkers do not distinguish between patients with sciatica and referred leg pain within a primary care population: results from a nested study within the ATLAS cohort

BackgroundThere is increasing interest in the role of pro-inflammatory cytokines in the pathogenesis of sciatica and whether these could be potential targets for treatment. We sought to investigate serum biomarker levels in patients with low back-related leg pain, including sciatica.MethodsPrimary care consulters aged > 18 with low back-related leg pain were recruited to a cohort study (ATLAS). Participants underwent a standardised clinical assessment, lumbar spine MRI and a subsample (n = 119) had samples taken for biomarker analysis. Participants were classified having: a) clinically confirmed sciatica or referred leg pain, and then subdivided into those with (or without) MRI confirmed nerve root compression due to disc prolapse. Seventeen key cytokines, chemokines and matrix metalloproteinases (MMPs) implicated in sciatica pathogenesis including TNFα and IL-6, were assayed in duplicate using commercial multiplex detection kits and measured using a Luminex suspension array system. Median biomarker levels were compared between the groups using a Mann Whitney U test. Multivariate logistic regression analysis was used to investigate the association between clinical measures and biomarker levels adjusted for possible confounders such as age, sex, and symptom duration.ResultsNo difference was found in the serum level of any of the 17 biomarkers tested in patients with (n = 93) or without (n = 26) clinically confirmed sciatica, nor between those with (n = 44) or without (n = 49) sciatica and MRI confirmed nerve root compression.ConclusionIn this cohort, no significant differences in serum levels of TNFα, IL-6 or any other biomarkers were seen between patients with sciatica and those with back pain with referred leg pain. These results suggest that in patients with low back-related leg pain, serum markers associated with inflammation do not discriminate between patients with or without clinically confirmed sciatica or between those with or without evidence of nerve root compression on MRI.

Periodontitis and Rheumatoid Arthritis: The Same Inflammatory Mediators?

The strict link between periodontitis (PD) and rheumatoid arthritis (RA) has been widely demonstrated by several studies. PD is significantly more frequent in RA patients in comparison with healthy subjects: this prevalence is higher in individuals at the earliest stages of disease and in seropositive patients. This is probably related to the role of P. gingivalis in inducing citrullination and leading to the development of the new antigens. Despite the many studies conducted on this topic, there is very little data available concerning the possibility to use the same biomarkers to evaluate both RA and PD patients. The aim of the review is to summarize this issue. Starting from genetic factors, data from literature demonstrated the association between HLA-DRB1 alleles and PD susceptibility, similar to RA patients; moreover, SE-positive patients showed simultaneously structural damage to the wrist and periodontal sites. Contrasting results are available concerning other genetic polymorphisms. Moreover, the possible role of proinflammatory cytokines, such as TNF and IL6 and autoantibodies, specifically anticyclic citrullinated peptide antibodies, has been examined, suggesting the need to perform further studies to better define this issue.

Proinflammatory Cytokines as Biomarkers for BOS, Death, or Retransplantation after Lung Transplantation

Purpose Chronic Lung Allograft Dysfunction (CLAD) is characterized by airway epithelial damage and fibrosis. The origin and initiation of fibrosis are poorly understood. We hypothesized that immune mediators in bronchoalveolar lavage (BAL) predict bronchiolitis obliterans syndrome (BOS), a form of CLAD, and poor survival. In a multi-center observational study, we investigated the role of proinflammatory cytokines as biomarkers for poor outcome after lung transplant (LTx). Methods In a 24-month, prospective, observational multi-center study, 61 children were recruited between 7/2009 and 4/2013 at 6 US pediatric LTx centers (CTOTC-03; NCT00891865). The immune suppression regimen was standardized across sites. BAL and serum were obtained at specified intervals. The primary composite outcome included: incidence of BOS or its histological manifestation obliterative bronchiolitis (OB), retransplant, or death. Serum and BAL samples were assayed with Luminex panels to detect 78 antigens. Cytokine expression patterns were analyzed, BOS was graded per ISHLT criteria. Univariable linear, repeated measures mixed models were used to model the relationship of each Log10 transformed cytokine with (1) the composite endpoint and (2) BOS or OB without death. Values not adjusted for multiple comparisons. Results 28 children met the composite endpoint vs. 33 remained healthy. With BOS/OB considered alone (n=16), IL23 (p=0.05), EGF (p=0.04), IL31 (p=0.04) and EOX (p=0.02) were significantly increased, whereas IL23 was the only cytokine significantly correlated to the composite endpoint (p=0.02). Conclusion Cytokines IL23, EGF, IL31 and EOX are associated with BOS/OB and linked to airway epithelial cell injury, particularly alveolar type 2 (AT2) cells, suggesting dysregulated repair and chronic inflammation after LTx contribute to BOS. Consistent with other studies that suggest BAL eosinophilia is a major feature of lung allograft rejection, our results found that EOX, a recruiter of eosinophils and Th2 lymphocytes were highly associated with BOS. Finally, IL-23 is pro-inflammatory cytokine linked with chronic inflammation and were significant in both analyses. These data suggest specific inflammatory pathways may be targeted to prevent BOS and improve outcome after LTx in children.

The innate immune response to allotransplants: mechanisms and therapeutic potentials.

Surgical trauma and ischemia reperfusion injury (IRI) are unavoidable aspects of any solid organ transplant procedure. They trigger a multifactorial antigen-independent inflammatory process that profoundly affects both the early and long-term outcomes of the transplanted organ. The injury associated with donor organ procurement, storage, and engraftment triggers innate immune activation that inevitably results in cell death, which may occur in many different forms. Dying cells in donor grafts release damage-associated molecular patterns (DAMPs), which alert recipient innate cells, including macrophages and dendritic cells (DCs), through the activation of the complement cascade and toll-like receptors (TLRs). The long-term effect of inflammation on innate immune cells is associated with changes in cellular metabolism that skew the cells towards aerobic glycolysis, resulting in innate immune cell activation and inflammatory cytokine production. The different roles of proinflammatory cytokines in innate immune activation have been described, and these cytokines also stimulate optimal T-cell expansion during allograft rejection. Therefore, early innate immune events after organ transplantation determine the fate of the adaptive immune response. In this review, we summarize the contributions of innate immunity to allograft rejection and discuss recent studies and emerging concepts in the targeted delivery of therapeutics to modulate the innate immune system to enhance allograft survival.

The haematological, proinflammatory cytokines and IgG changes during an ovine experimental theileriosis.

Malignant ovine theileriosis is caused by Theileria lestoquardi, which is highly pathogenic in sheep. Theileriosis involves different organs in ruminants. Little is known about the role of proinflammatory cytokines in the pathogenesis of T. lestoquardi infection. The aim of this study was to measure concentration changes of proinflammatory cytokines and immunoglobulin G (IgG) during an ovine experimental theileriosis and correlate it with clinical and haematological parameters. During an experimental study, seven healthy Baluchi sheep (four females and three males) about 6–8 months old were infected with T. lestoquardi by feeding of infected unfed ticks on the sheep’s ears. The infected sheep were clinically examined during the study and blood samples were collected on days 0, 2, 5, 7, 10, 12, 14, 17 and 21. The haematological parameters were analysed by an automatic veterinary haematology cell counter and the inflammatory cytokines interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and IgG were measured by enzyme-linked immunosorbent assay. All infected sheep had temperatures above 40 °C on days 3–4 post infection (PI). The maximum temperature was noted on day 7, and it remained high until day 21. The parasitaemia of T. lestoquardi infection increased from 0.01% (day 7 PI) to 3.3% (day 21 PI). The mean white blood cell (WBC), red blood cell (RBC), lymphocyte, neutrophil and platelet values slightly increased on day 2 PI and decreased by day 17 and day 21 PI. The percentage parasitaemia and fever had a negative correlation with the numbers of WBCs, RBCs, lymphocytes, neutrophils and platelets. The serum concentration of IL-6, TNF-α and IFN-γ cytokines increased and peaked on day 12 and thereafter decreased to levels lower than 0. Out of all tested cytokines, the concentration of IL-6 was significantly higher, as early as day 2 PI. No significant changes were observed for the IgG levels during the course of disease. A significant and strong correlation was observed between IL-6, TNF-α and IFN-γ values and a moderate correlation between IL-6 and the numbers of lymphocytes in the present study. A strong correlation was determined between the percentage parasitaemia and haematological parameters in T. lestoquardi-infected sheep. In addition, preliminary results indicate that the measurement of the serum concentrations of IL-6 in combination with haematological parameters could be considered a good marker to estimate the pathogenicity of T. lestoquardi strain.

Proinflammatory Cytokines and Skin Wound Healing in Mice

Skin wound healing is subject to an intricate regulation, involves many cell populations and molecular mediators, and is one of the key mechanisms that ensures the barrier functions of the skin and the maintenance of body homeostasis. The efficiency of this process is largely determined by the balance of proinflammatory and proregenerative signals, which are mediated by cytokines. The review summarizes the latest data on the role of proinflammatory cytokines, mainly tumor necrosis factor (TNF), interleukin 6 (IL-6), interleukin 1 (IL-1), and interferons (IFNs), in skin wound healing, including those obtained with the use of genome editing techniques and methods of reverse genetics to establish relevant animal models. The roles that proinflammatory cytokines play at various stages of skin regeneration are discussed for both normal state and systemic pathologies, such as diabetes. Promising approaches to treating poorly healing wounds are summarized.

The role of pro-inflammatory cytokines in the pathogenesis and progression of neoplasms

Cytokines play an important role in the functioning of the immune system. Studies have reported an increased secretion of inflammatory cytokines by the neoplasms. Inflammation plays a role in the pathogenesis of various diseases; it is also a risk factor for the development and progression of a neoplasm, as exemplified by the development of cancer in the region of the head and neck in response to chronic inflammation caused by irritants present, e.g. in cigarette smoke. Cytokines (IL-1 beta, IL-6, TNF, IL-8, IL-17), which take part in the inflammatory response and are, therefore, strongly involved in the development of cancer. The combined action of cytokines produced by the neoplastic cells via multiple mechanisms, modulates cell response of the host immune system. Clinical observations suggest that cancer patients show a progressive disorder of the immune system, resulting in tumor progression. The mechanisms conducive to the weakening or lack of an immune response to neoplastic antigens contribute to the severity of the invasion of cancerous lesions. Although mechanisms that occur between tumor cells, the micro-environment of the tumor and immune cells of the host are not thoroughly known, previous research point to the importance of this interaction in oncogenesis, which may ultimately affect the prognosis.

Inhibition of adiposity and related metabolic disturbances by polyphenol-rich extract of Boswellia serrata gum through alteration of adipo/cytokine profiles.

The role of proinflammatory cytokines in adiposity is well established. The anti-inflammatory and antihyperglycemia effects of Boswellia serrata (B. Serrata) gum have been demonstrated by many investigators. The present study aimed to investigate the anti-obesity potential of B. serrata extract. The effects of B. serrata extract on lipase activity and acute food intake were investigated. The present study aimed to investigate the anti-obesity potential of B. serrata extract. The effects on lipase activity and acute food intake were investigated. Body weight changes, biochemical and histopathological markers were demonstrated in rats fed a high-fat diet. Boswellia serrata extract inhibited alterations in pancreatic lipase activity, but orlistat was more efficacious. B. serrata and ephidrene, but not orlistat, significantly suppressed cumulative food intake in mice. In obese rats, B. serrata or orlistat significantly decreased weight gain and weight of visceral white adipose tissue. B. serrata-treated animals exhibited a significant reduction in serum glucose, TC, TG, LDL-C, FFA, IL-1β, TNF-α, insulin and leptin levels of obese rat groups while HDL-C and adiponectin levels were significantly increased by orlistat or B. serrata extract. Histopathological examination of the liver revealed that B. serrata was more effective than orlistat in alleviating steatosis and adipocyte hypertrophy shown in obese control rats. Boswellia serrata is as effective as orlistat in preventing obesity, hyperlipidemia, steatosis and insulin resistance. These actions may be mediated by suppression of food intake and decrease levels of TNF-α, IL-1β and leptin resistance along with increasing adiponectin.

Endotoxinemia contributes to steatosis, insulin resistance and atherosclerosis in chronic hepatitis C: the role of pro-inflammatory cytokines and oxidative stress.

Endotoxin is a component of the outer membrane of gram-negative bacteria that live in the intestine. Endotoxinemia is reported in non-alcoholic fatty liver disease and in cirrhotic patients, causing various biological and clinical effects in the host. It is not known whether endotoxinemia occurs in chronic hepatitis C patients (CHC), therefore we evaluated the occurrence of endotoxinemia and its effect on inflammation, liver damage, insulin resistance (IR) and atherosclerosis. Consecutive CHC patients assessed by liver biopsy were enrolled. Endotoxinemia was evaluated by LAL test. IR was estimated by HOMA-IR. Serum TNF-α, IL-8, adiponectin and MCP-1 were measured with ELISA tests. Oxidative stress was estimated by circulating IgG against malondialdehyde adducts with human serum albumin (MDA-HAS). Carotid atherosclerosis was assessed by ultrasonography. Endotoxinemia was found in 60% of the 126 patients enrolled. A serum level-dependent association between endotoxinemia, steatosis (p < 0.001) and HOMA-IR (p < 0.006) was observed. Patients with endotoxinemia showed significant increase in TNF-α and IL8 levels. TNF-α correlated with steatosis (p< 0.001) and HOMA-IR (p < 0.03), whereas IL8 correlated with steatosis (p = <0.001), TNF-α (p < 0.04) and atherosclerosis (p < 0.01). The highest levels of endotoxinemia were associated with oxidative stress and a higher prevalence of carotid atherosclerosis. Multivariate logistic regression analysis showed that the independent factors associated with endotoxinemia were hepatic steatosis, HOMA-IR, IL8 and MDA-HAS. Endotoxinemia occurs with high frequency in CHC patients and contributes to the development of hepatic steatosis, IR and atherosclerosis through increased pro-inflammatory cytokines and oxidative stress. Anti-endotoxin treatment could be of clinical relevance.

Restorative effect of resveratrol on expression of endothelial and neuronal nitric oxide synthase in cavernous tissues of chronic unpredictable mild stress-exposed rats: an impact of inflammation.

We investigated the effect of resveratrol on endothelial and neuronal nitric oxide synthase (eNOS and nNOS) expression in the corpus cavernosum from chronic unpredictable mild stress (CUMS)-exposed rats in order to examine possible role of proinflammatory cytokines, which might play a role on erectile dysfunction (ED). Rats were randomly and equally divided into fourgroups such as control,control+resveratrol, CUMS and CUMS + resveratrol (20 mg/kg/day, i.p/8 weeks). Sucrose intake and forced swimming tests were used to evaluate depressive-like behaviors. nNOS, eNOS expressions, inflammatory markers, corticosterone and testosterone levels were analyzed either in blood samples and/or penile tissues. CUMS-exposed rats displayed depressive-like behaviors, reduced penile nNOS and eNOS expressions, and serum testosterone levels and enhanced serum and penile tissue levels of proinflammatory markers compared to controls. Resveratrol reversed depressive-like behaviors and suppressed serum and penile levels of proinflammatory markers, increased nNOS and eNOS expressions and testosterone levels in CUMS-exposed rats. Resveratrol exerted antidepressant-like effects and protected the development of CUMS-induced impairment of cavernosal eNOS and nNOS expressions associated with ED, which might be related to its anti-inflammatory action.