Role Of Inflammatory Cytokines Research Articles

Venlafaxine inhibits naloxone-precipitated morphine withdrawal symptoms: Role of inflammatory cytokines and nitric oxide.

Opioid-induced neuroinflammation plays a role in the development of opioid physical dependence. Moreover, nitric oxide (NO) has been implicated in several oxidative and inflammatory pathologies. Here, we sought to determine whether treatment with venlafaxine during the development of morphine dependence could inhibit naloxone-precipitated withdrawal symptoms. The involvement of neuro-inflammation related cytokines, oxidative stress, and L-arginine (L-arg)-NO pathway in these effects were also investigated. Mice received morphine (50 mg/kg/daily; s.c.), plus venlafaxine (5 and 40 mg/kg, i.p.) once a day for 3 consecutive days. In order to evaluate the possible role of L-arg-NO on the effects caused by venlafaxine, animals received L-arg, L-NAME or aminoguanidine with venlafaxine (40 mg/kg, i.p.) 30 min before each morphine injection for 3 consecutive days. On 4th day of experiment, behavioral signs of morphine-induced physical dependence were evaluated after i.p. naloxone injection. Then, brain levels of tissue necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), brain-derived neurotrophic factor (BDNF), NO and oxidative stress factors including; total thiol, malondialdehyde (MDA) contents and glutathione peroxidase (GPx) activity were determined. Co-administration of venlafaxine (40 mg/kg) with morphine not only inhibited the naloxone-precipitated withdrawal signs including jumping and weight loss, but also reduced the up-regulation of TNF-α, IL-1β, IL-6, NO and MDA contents in mice brain tissue. However, repeated administration of venlafaxine inhibited the decrease in the brain levels of BDNF, total thiol and GPx. Pre-administration of L-NAME and aminoguanidine improved, while L-arg antagonized the venlafaxine-induced effects. These results provide evidences that venlafaxine could be used as a candidate drug to inhibit morphine withdrawal through the involvement of inflammatory cytokines and l-arginine-NO in mice.

Crosstalk between cytokine profile, redox, and iron status in β-Thalassemia: relation to frequency/duration of blood transfusion

β-Thalassemia, a blood disease instigated by mutations in β-globin genes or their regulatory regions. Infectious complications, immune abnormalities and iron overload related organ damage are the chief causes of morbidity and mortality. The role of inflammatory cytokines in the pathophysiology of β-thalassemia is still indistinct, so the present study aimed to evaluate immune-inflammatory and redox status in β-thalassemia and their relation to iron status, frequency/duration of blood transfusion. Seventy β-Thalassemia patients (35 β-thalassemia major; 35 β-thalassemia intermedia) and twenty age and sex-matched healthy controls were included. Interleukin4 (IL4), Interleukin10 (IL10), Interleukin 8 (IL8), and Interleukin 13 (IL13) levels were immunoassayed in addition to iron, hematological and redox status assessment. Significantly increased iron, ferritin, IL8, IL13 levels (p value ˂0.001), meanwhile, decreased IL10 level, total anti-oxidant (TAC) and iron binding capacities were observed in β-thalassemia major compared with β-thalassemia intermedia and control groups (p value ˂0.001) . IL4 level was decreased in patients group compared to control. Positive correlation was found between malondialdehyde (MDA), IL8, IL13 and iron load, transfusion frequency/duration, total leucocyte count and lymphocyte (%). Meanwhile, negative correlation was found with IL4, IL10, and TAC. Multiple blood transfusions increased iron stores which may critically impair the immune-regulatory balance with disturbed redox status and cytokine profile.

The role of inflammatory cytokines in the pathogenesis of pulmonary arterial hypertension

The role of inflammatory cytokines in the pathogenesis of pulmonary arterial hypertension

Role of Inflammatory Cytokines and Immune Reactive Molecules in Pathogenesis of Streptococcus Agalactiae in Aborted Healthy Women

Streptococcus. agalactiae has been appearing as a vital human pathogen and a gradually important cause of aggressive infections in immunocompromised adults and older, the aim of the study was to find the effect of inflammatory cytokine (interleukin 8) and immune reactive molecules (CD79 and CD54 molecules) on pathogenesis of S. agalactiae that isolated from aborted women. A total of 100 aborted women aged between (18–42) years, were involved in this study. Placentas specimens were cultured to isolate the Streptococcus agalactiae, the level of cytokine in the serum was measured by commercial ELISA tests, while CD molecules was estimated by immunohistochemistery assay. Our results showed that there was streptococcal isolates from Placentas specimens, Specific isolation and identification were done for S. agalactiae. Significant difference could be found in serum levels of inflammatory cytokine (P≤ 0.05) between these two investigated groups (infected and uninfected with S. agalactiae) in addition to high expression for CD79 and CD54 in infected women as compare with non S. agalactiae infected women.

Glial mechanisms underlying major depressive disorder: Potential therapeutic opportunities.

Major depressive disorder is a severe and the most prevalent form of neuropsychiatric disorder that affects millions of individuals worldwide. The current treatment focuses on brain monoamine hypothesis and conventional antidepressants that inhibit the reuptake of monoamine neurotransmitters to elevate synaptic monoamine concentrations to interact with postsynaptic receptors. However, many people with major depressive disorder fail to respond to conventional therapies experiencing relapse and significant functional impairment. It is increasingly recognized that glia-associated inflammatory mechanisms contribute to the pathophysiology of major depressive disorder. Furthermore, microglial nicotinic cholinergic mechanisms were recently proposed to play a critical role in major depressive disorder-linked inflammatory processes. In this review, we will provide recent advances on glial dysfunctions, the role of inflammatory cytokines, transcription factors, and brain derived neurotrophic factor underlying the pathophysiology of major depressive disorder. We will also evaluate and discuss the anti-inflammatory effects of nicotinic acetylcholine receptor positive allosteric modulators and glial nicotinic receptor-mediated mechanisms that might be responsive to potential pharmacologic interventions. Overall, these important, but underappreciated, roles of brain glial targets and mechanisms might offer new therapeutic opportunities for major depressive disorder.

Micro-RNA 18b and interleukin 17A profiles in relapsing remitting multiple sclerosis

BackgroundThe involvement of micro RNAs (miRNAs) in multiple sclerosis (MS) has been recently explored. Up-regulated miRNAs may play critical roles in MS pathogenesis and may be used as a signature for MS. Besides, the role of inflammatory cytokines has been long established with recent focus on interleukin-17 (IL-17). ObjectiveTo evaluate the level of expression miR-18b in relation to IL-17A in relapsing remitting (RR) MS patients during relapse and remission Subjects and methodsTwenty-eight RRMS patients and 26 age and sex matched control subjects were included. Serum miR-18b was assessed by quantitative real-time PCR, and serum level of IL-17A was measured by ELISA. ResultsSerum miR-18b expression was higher in relapse compared with remission and with controls (24.8 ± 21.91 vs 2.49 ± 0.97 vs 1 ± 0.36 respectively; P < 0.001). Serum IL-17Awas higher in MS patients during relapse than during remission and controls (8.49 ± 1.26 vs 5.78 ± 2.27 vs 4.18 ± 2.13, respectively; P < 0.001). No correlations existed between miR-18 and IL-17 in MS patients during relapse (r = 0.35; P = 0.22) or remission (r = 0.340; P = 0.234). ConclusionUpregulation of miR-18 during relapse in patients with RRMS points to a possible contribution to the pathogenesis of the inflammatory process in MS. The lack of a significant correlation between upregulated miR-18 and IL-17A implicates that the influence of miR-18 may be exhibited via another inflammatory pathway.

The Role of Inflammatory Cytokines in Cardiac Arrest.

Post-cardiac arrest syndrome (PCAS) is characterized by systemic ischemia/reperfusion injury, anoxic brain injury, and post-arrest myocardial dysfunction superimposed on a precipitating pathology. The role of inflammatory cytokines in cardiac arrest remains unclear. We aimed to describe, with an emphasis on clinical applications, what is known about the role of inflammatory cytokines in cardiac arrest. A PubMed literature review was performed for relevant articles. Only articles in English that studied cytokines in patients with cardiac arrest were included. Cytokines play a crucial role in the pathogenesis of PCAS. Following cardiac arrest, the large release of circulating cytokines mediates the ischemia/reperfusion injury, brain dysfunction, and myocardial dysfunction seen. Interleukins, tumor necrosis factor, and matrix metalloproteinases all play a unique prognostic role in PCAS. High levels of inflammatory cytokines have been associated with mortality and/or poor neurologic outcomes. Interventions to modify the systemic inflammation seen in PCAS continue to be heavily studied. Currently, the only approved medical intervention for comatose patients following cardiac arrest is targeted temperature management. Medical agents, including minocycline and sodium sulfide, have demonstrated promise in animal models. The role of inflammatory cytokines for both short- and long-term outcomes is an important area for future investigation.

A case-control study of the genetic polymorphism of IL6 and HAPE risk in a Chinese Han population.

The role of inflammatory cytokines in High-altitude pulmonary edema (HAPE) remains unclear. The purpose of this study was to evaluate the role of IL4 and IL6 gene polymorphism in the development of HAPE in Chinese people. In the present study, we screened ten polymorphisms of IL4 and IL6 gene in 265 HAPE and 303 healthy volunteers. Genotypes were determined using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression. Two single-nucleotide polymorphisms (SNPs) in the IL6 gene were significantly associated with HAPE. Rs1800796 and rs1524107 (G vs C, OR=1.31, 95%CI=1.01-1.69, P=.041 and T vs C, OR=1.35, 95%CI=1.05-1.74, P=.020, respectively). However, there did not found any association for IL4 gene. Inflammatory cytokines may play a role in the progress of HAPE. These polymorphisms could be genetic markers for predicting the susceptibility to HAPE.

Influence of IL-6, IL-10, IFN-γ and TNF-α genetic variants on susceptibility to diabetic kidney disease in type 2 diabetes mellitus patients

Background: Data from previous studies on the role of inflammatory cytokines as biomarkers for diabetic kidney disease (DKD) are contradictory. The association of a particular inflammatory cytokine single nucleotide polymorphism (SNP) with susceptibility to DKD has not been consistently replicated. We aimed to investigate the utility of inflammatory cytokines as biomarkers for DKD in type 2 diabetes mellitus (T2DM) patients. Association of inflammatory cytokine gene SNPs with the development of DKD was also explored.Subjects and Methods: One hundred and fifty-nine Kuwaiti subjects were recruited in this study, including 50 T2DM patients without DKD, 67 diabetic DKD patients and 42 healthy subjects. Plasma levels of interleukin-6 (IL-6), IL-10, interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) were measured by enzyme-linked immunosorbent assays. Nine SNPs, including 2 SNPs in IL-6, 3 SNPs in IL-10, 1 SNP in IFN-γ and 3 SNPs in TNF-α, were genotyped using TaqMan SNP genotyping assays.Results: Diabetic DKD patients showed higher IL-6, IL-10, IFN-γ and TNF-α levels than those without DKD. Diabetic DKD patients had a significantly higher frequency of IL-10 − 1082 A allele than those without DKD (p = 0.001). No significant association of IL-6 − 174/−597 haplotypes with DKD risk was detected (p = 0.188). Distribution of IL-10 − 592/−819/−1082 haplotypes differ significantly between T2DM patients with/without DKD (p = 0.014). Diabetic DKD patients had a significantly lower frequency of IL-10 − 592C/−819C/−1082G haplotype than those without DKD (p = 0.002).Conclusions: Although inflammatory cytokine genotypes and, more importantly, haplotypes may have the potential to identify those patients at risk of DKD, hence, improving DKD predisposition prediction, further investigations regarding their real clinical significance is warranted in a large cohort of patients.

The Role of Inflammatory Cytokines in Creating T Cell Exhaustion in Cancer.

Secreted inflammatory cytokines are considered as critical mediators in the tumor microenvironment. Cancer cells play a significant role in the differentiation of effector T cells to exhausted T cells through mediator production. Effector T cells that undergo tumor microenvironment become terminally differentiated into exhausted T cells. These changes create an opportunity for tumorigenesis and invasion of cancer cells. Despite having some characteristics of effector T cells, the exhausted T cells lose their antitumor properties. In this article, the phenotypes and function of exhausted T cells were reviewed and the expression pattern of inflammatory cytokines in tumor tissues and peripheral blood of cancer patients were described. Additionally, the effects of inflammatory cytokines on intracellular factors and signals of T lymphocyte cells were explained. In conclusion, the authors referred to probable approaches that could be used to improve the antitumor activity of T cells and intervention into T cell exhaustion.

Effect of certain trimethoxy flavones on paclitaxel - induced peripheral neuropathy in mice

BackgroundThe anti - nociceptive effect of 7, 2′, 3′ – trimethoxy flavone, 7, 2′, 4′ – trimethoxy flavone, 7, 3′, 4′ – trimethoxy flavone and 7, 5, 4′ – trimethoxy flavone against inflammatory, neurogenic and thermal pain in mice was reported earlier. The present study was designed to investigate the effect of the above trimethoxy flavones in amelioration of peripheral neuropathy induced by paclitaxel. MethodsPeripheral neuropathy was induced in mice by administration of a single i.p. dose (10mg/kg) of paclitaxel. The manifestations of peripheral neuropathy such as tactile allodynia, cold allodynia and thermal hyperalgesia were assessed 24h later by employing hair aesthesiometer test, acetone bubble test and hot water tail immersion test respectively. Further, the role of inflammatory cytokines like TNF – α, IL - 1β and free radicals in the action of trimethoxy flavones was investigated using in vitro assays. ResultsThe test compounds dose dependently attenuated paclitaxel - induced tactile allodynia, cold allodynia and thermal hyperalgesia in mice. The test compounds inhibited TNF – α, IL - 1β and free radicals in a concentration dependent manner. ConclusionThe investigated trimethoxy flavones attenuated paclitaxel – induced peripheral neuropathy in mice. The inhibition of cytokines and free radicals in addition to many neuronal mechanisms reported earlier may contribute to this beneficial effect.

Role of Inflammatory Cytokines during Lung Cancer Progression: A Review

The role of inflammation and inflammatory microenvironment in the development of cancer was described as early as 1863 by Rudolf Virchow. The host immune system performs constant patrolling in the body for foreign invaders and aberrant cells in order to destroy them, a process generally called as immunosurveillance. Inflammation is a beneficial response activated to help during tissue injury and act against pathogenic agents. However if inflammation is unregulated, it can become chronic inducing malignant cell transformation in the surrounding tissues. Inflammation increase the bioactive molecules in the tumor microenvironment including cytokines, growth factors and chemokines, matrix modifying enzymes such as matrix metalloproteinases and can increase the risk of cancer. Several disease conditions illustrate the link between inflammation and cancer such as endometriosis, chronic prostatitis, chronic gastritis, inflammatory bowel diseases and primary sclerosing cholangitis which eventually leads to one or the other forms of cancer. This article reviews the effects of major inflammatory cytokines which are involved in lung cancer progression.

The evaluation of the serum level of IL-10 in OLP patients

Lichen planus (LP) is an autoimmune chronic inflammatory disease. Interleukin 10 (IL-10) can inhibit the synthesis of pre-inflammatory cytokines. Regarding the role of inflammatory cytokines in lichen planus patients, evaluating the serums level of IL-10 in such patients can declare the potential role of this cytokine. In this study, 44 serum samples from patients with lichen planus and 44 serum samples from healthy participants were collected during 2015–2016. The patients with clinical or histopathological confirmation for oral lichen planus (OLP) were included in the case group, and the healthy patients were recruited in the control group. The serum level of IL-10 was measured by ELISA kits. In this cross-sectional study between 2015 and 2016, the serum level of IL-10 was measured in 53 females (60.22%) and 35 males (39.77%). In the lichen planus group, 44 subjects and in the control group, 44 healthy participants were enrolled. The mean serum level of IL-10 in oral lichen planus patients was reported as 3.68 ± 3.44 pg/ml and this was 0 ± 0 pg/ml in the healthy control group. The mean serum level of IL-10 in oral lichen planus patients was significantly more than the mean serum level of IL-10 in the control participants (P = 0.042).There was no relation between serum level of IL-10 in OLP patients and age (P = 0.771) and sex (P = 0.547) of participants. The findings indicated significant difference between the serum level of IL-10 and types of oral lichen planus lesions (P < 0.001). This study indicated that significant elevation of IL-10 in OLP patients might be important in immunomodulating of this disease, although the exact mechanism is not clear.

Abstract 4752: Inflammatory cytokines and hematopoietic stem cells are associated with fatigue and insomnia in breast cancer patients undergoing adjuvant radiation therapy

Abstract Introduction: Breast cancer patients undergoing adjuvant radiation therapy (RT) commonly experience fatigue and insomnia. We previously reported that this fatigue is associated with a reduction in circulating hematopoetic stem cells (HSCs; CD34+); the role of inflammatory cytokines in mediating this process however, has not been clearly elucidated. Materials and Methods: Breast cancer patients (n=147) undergoing adjuvant RT underwent phlebotomies for analysis of CD34+, CD45+, CBC, as well as 17 inflammatory cytokines using a multiplexed ELISA platform, during 5 time points: prior to RT (D1); after Days 2, 5, during final week of RT (D2, D5, and Df, respectively); as well as one month post RT-completion (M1). At the same time, patients also completed questionnaires for the multidimensional fatigue inventory (MFI-20), hospital anxiety and depression scale (HADS), and insomnia severity index (ISI). Results: General fatigue worsened over the course of RT from D1 to Df, being most severe at the end of treatment (Df), but returned to baseline at M1. This trend was statistically significant (p&amp;lt;0.001), after adjusting for anxiety, depression, and insomnia. The levels of CD34+, CD45+, white blood cell, as well as lymphocyte counts decreased over time, with the lowest levels observed at Df (p&amp;lt;0.001 for all). General fatigue correlated inversely with CD34+ counts (adjusted for anxiety, depression, and ISI), and was also negatively associated with hemoglobin, RBC, and lymphocyte counts (p&amp;lt;0.001 for all). There was also a significant correlation between increasing insomnia with lower CD34+, CD45+, white blood cell and lymphocyte counts (all p&amp;lt;0.05). Serum concentrations of TGF-β1, MCP-1, MMP-2, IL-1ra and IFN-α2a changed significantly during RT (p&amp;lt;0.01 for all), with either the highest or lowest levels observed at Df. Increasing levels of MCP-1, TNF-RII and TNF-a were associated with worsening general physical fatigue, reduced activity, decreased motivation, as well as increased insomnia (p&amp;lt;0.001 for all). Furthermore, there appeared a trend between increasing MMP-2, as well as decreasing IL-1ra and TGF-β1, with reduced CD34+, CD45+, WBC and lymphocyte counts (p&amp;lt;0.001). The 52 patients who received prior adjuvant chemotherapy demonstrated significantly higher fatigue, anxiety, and insomnia scores. Conclusions: This study represents one of the most comprehensive longitudinal evaluations of the effects of RT on fatigue and insomnia, demonstrating that this process was associated with increased levels of the pro-inflammatory cytokines MCP-1, TNF-RII and TNF-a, and reductions in circulating HSCs and other hematologic parameters. Further understanding of the roles of these cytokines would provide important insights into both quality of life for patients undergoing cancer therapies, as well as the interactions between RT with immunotherapy. Citation Format: Wei Shi, Kathy Han, Madeline Li, Justin Williams, Megan McCusker, Jie Su, Wei Xu, Scott Bratman, Kenneth Yip, Fei-Fei Liu. Inflammatory cytokines and hematopoietic stem cells are associated with fatigue and insomnia in breast cancer patients undergoing adjuvant radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4752. doi:10.1158/1538-7445.AM2017-4752

Treatment response to etanercept in methotrexate refractory juvenile idiopathic arthritis: an analysis of predictors and long-term outcomes.

The aim of the study is to evaluate the long-term outcomes, predictors, and the role of inflammatory cytokines in methotrexate (MTx) refractory juvenile idiopathic arthritis (JIA) patients. This is a retrospective cohort study. MTx refractory JIA patients who received etanercept as their first biological agent in National Taiwan University Hospital (NTUH) were enrolled. Patients were classified into remission group, non-remission group, relapsing group, and non-relapsing group according to the criteria of disease remission and disease flares defined by Wallace et al. We compared the differences in the baseline data, therapeutic responses, time to etanercept tapering, and inflammatory cytokine (IL-12p70, TNF-α, IL-10, IL-6, and IL-1β) levels between these groups. Among the 58 patients, 30 (52%) reached remission. Seventeen of the 30 patients had episodes of disease flares. We found that more patients in the remission group achieved ACR pediatric 70 response at the fourth month after etanercept treatment (p<0.002). When comparing the relapsing group and non-relapsing group, we found that patients were more likely to have disease flares if it took longer to achieve remission (p=0.0008). Besides, etanercept was tapered earlier in the non-relapsing group (p=0.0006). There was no significant difference in levels of inflammatory cytokine between groups. No parameter before treatment could be used as a single predictor of long-term outcomes. However, ACR pediatric 70 response at the fourth month after etanercept treatment might predict disease remission. Besides, patients who achieved remission more rapidly were less likely to have disease flares.

Association of fatigue and insomnia with inflammatory cytokine and hematopoetic stem cell levels in breast cancer patients undergoing adjuvant radiation therapy.

e12048 Background: Fatigue and insomnia are frequent conditions experienced by breast cancer patients during adjuvant radiation therapy (RT). Our group reported that fatigue correlates with reduced CD34+ circulating hematopoetic stem cell (HSC) levels. Our current study examined the role of inflammatory cytokines in mediating fatigue and insomnia following adjuvant RT. Methods: Phlebotomies were conducted on 148 breast cancer patients undergoing adjuvant RT at five time points: prior to RT (D1), after two (D2) and five (D5) days of treatment, during the final week of RT (Df), and one month post-RT completion (M1). CD34+, CD45+, circulating blood cell (CBC), and 17 inflammatory cytokine levels were assessed. Patients also completed questionnaires at each time point, including the multidimensional fatigue inventory (MIF-21), insomnia severity index (ISI), and hospital anxiety and depression scale (HADS). Results: CD34+, CD45+ and CBC levels decreased during treatment with adjuvant RT, with the lowest levels observed at Df (p&lt;0.001). General fatigue significantly worsened throughout treatment from D1 to Df, returning to baseline at M1, (p&lt;0.001; adjusted for insomnia, depression and anxiety). General fatigue worsened as CD34+ counts, hemoglobin and CBCs increased (p&lt;0.001). Insomnia increased with reduced CD34+, CD45+ and CBCs (p&lt;0.05). TGF-β1, MCP-1, MMP-2, IL-1ra and IFN-α2a cytokine expression varied throughout RT (p&lt;0.01), most significantly at Df. Elevated MCP-1, TNF-RII and TNF-a levels correlated with worsening general fatigue, increased insomnia, and reduced activity and motivation (p&lt;0.001). MMP-2 increased as IL-1ra, CD34+, CD45+ and CBC counts decreased (p&lt;0.001). Further, the 52 patients who received prior adjuvant chemotherapy had elevated levels of fatigue, insomnia and anxiety, which correlated with high HSCs levels. Conclusions: Our findings demonstrate that fatigue and insomnia are associated with reduced HSCs and increased MCP-1, TNF-RII and TNF-a pro-inflammatory cytokines. This examination of the effect of RT on fatigue and insomnia is one of the most comprehensive longitudinal clinical evaluations of its kind.

Vasoprotective Actions of Chronic Vagal Nerve Stimulation in Hypertensive Rats – Role of inflammatory cytokines and vascular migration of inflammatory cells

In a previous study we demonstrated that four weeks of chronic vagal nerve stimulation (VNS) in stroke‐prone spontaneously hypertensive rats (SHR‐SP) on high‐salt diet prevents progression of endothelial dysfunction and aortic stiffening. This study was designed to test the hypothesis that anti‐inflammatory effects (e.g., reduced activation of inflammatory cells in the spleen, less vascular migration of inflammatory cells) of VNS contribute to these vasoprotective actions of chronic VNS. Aortic collagen I content, determined by immunohistochemistry, was less in SHR‐SP with VNS (n=8) than in sham‐stimulated SHR‐SP (Sham, n=8), confirming the effects of chronic VNS on aortic stiffening. Furthermore, aortic collagen I content correlated with serum levels of the pro‐inflammatory cytokines interleukin‐1 beta (IL‐1β, R=0.77, n=11, P&lt;0.01) and tumor necrosis factor‐alpha (TNF‐α, R‐0.55, n=11, P=0.08). Protein content of the pro‐inflammatory cytokines interleukin‐5 (IL‐5), macrophage inflammatory protein‐1 alpha (MIP‐1α), and TNF‐α was reduced in spleens from SHR‐SP with VNS compared to Sham (IL‐5: 0.35±0.02 vs. 0.69±0.11 pg/mg; MIP‐1α: 0.91±0.04 vs. 1.44±0.13 pg/mg; TNF‐α: 0.18±0.02 vs. 0.28±0.05 pg/mg; n=3 for both groups). Finally, preliminary data based on aortic staining for CD3 (T‐cells), CD45 (leukocytes), and CD68‐positive (macrophages) cells suggest less migration of inflammatory cells into the aorta in VNS compared to Sham (CD3: 25±1% vs. 62±5%; CD45: 28±18% vs. 53±3%; CD68: 23±6% vs. 44±11%; n=2 for both groups; % values are positively stained cells relative to all cells identified by DAPI staining of the cell nuclei). Collectively, these data suggest that reduced splenic activation of inflammatory cells and less vascular migration of inflammatory cells contribute to the vasoprotective actions of chronic VNS in this rat model of severe hypertension.Support or Funding InformationSupported by a pilot grant from the University of Iowa Hospitals and Clinics Center for Hypertension Research.

IL‐6 modulates cardiac muscle proteostasis and anti‐oxidative capacity post‐burn

Heart failure is the number one cause of death in severely burned patients. Burn‐induced cardiac dysfunction includes increased cardiac work, tachycardia and increased energy expenditure. Burn injury induces a surge in catecholamine and cytokines levels that lasts up to 3 years post injury. While cardiac dysfunction has been associated with stimulation of the β‐adrenergic receptors (β‐ARs) by catecholamines, the role of inflammatory cytokines in the cardiac muscle function is still unclear. We have reported that burn injury alters the beta‐adrenergic signaling in the heart at 7 days post‐burn. In another study, we have shown that burn injury induces atrophy of the diaphragm muscle through activation of the IL‐6/JAK/Stat pathway.Male wild‐type and interleukin 6 knockout mice (IL‐6 KO) were subjected to a 30% total body surface area full‐thickness burn. Animals were sacrificed 10 days post injury. The hearts were isolated and western blotting performed to analyze the role of JAK/Stat signaling pathways and antioxidant enzymes in cardiac muscle proteostasis post‐burn.Burn injury significantly increases Stat‐3 phosphorylation at Ser 727 in the WT (p&lt;0.05) but not in the IL‐6‐KO animals. Stat‐3 phosphorylation at tyrosine705 (Y705) was activated in the cardiac muscle of both the WT (p&lt;0.05) and IL‐6 KO (p&lt;0.05) mice post‐burn. At basal levels, p‐Stat‐3(Y705) was higher in the control IL‐6 KO than the control WT animals (p&lt; 0.05). P‐Stat‐3 (Y705) levels were also higher in L‐6 KO burned animals compared to WT burned animals (p&lt;0.01). The protein levels of antioxidant enzymes SOD‐2 and catalase were significantly decreased post‐burn in the WT (both p&lt;0.05) but not in the IL‐6 KO animals.These data suggest that the molecular mechanisms regulating cardiac muscle proteostasis and anti‐oxidative capacity following burn injury are altered in the IL‐6‐KO mice supporting the role of IL‐6 as a critical mediator in these processes.Support or Funding InformationThis study was supported by grants from the National Institute of Health (P50‐GM60338, R01‐GM56687, and T32‐GM8256, NIH R01 GM 112936‐01, UL1TR000071), Shriners Hospitals for Children (71008, 71001 and 84080), and the Shriners Hospital for Children fellowship for AE (SHC 84202).

Roles of inflammatory cytokines in acute graft-versus-host disease and their mechanisms

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for the treatment of various malignant and non-malignant hematological diseases. Acute graft-verse-host-disease (aGVHD), a major complication following allo-HSCT, is one of the predominant causes of GVHD-related mortality. The development of aGVHD is a typical pathologic process with the release of inflammatory cytokines in great quantities, resulting in the occurrence of cytokine storm and causing specific pathological damages by attacking the recipient organ. Therefore, identification of biomarkers specific for aGVHD offers promise to the treatment of aGVHD. In this review, we summarizes the functions of several typical inflammatory cytokines, including IL-1β, IL-6, IL-17A and IL-10, and their mechanisms in the development of aGVHD in order to provide references for the prevention and treatment of aGVHD. Key words: aGVHD; Proinflammator factor; Suppressive factor; Biomarkers; Predictive value

Rheumatoid Arthritis in Sickle-Cell Population: Pathophysiologic Insights, Clinical Evaluation and Management.

The advent of hydroxyurea and advanced medical care, including immunizations has led to improved survival among patients with Sickle Cell Disease (SCD). This prolonged survival however, introduces a chronic inflammatory disorder, Rheumatoid Arthritis (RA), which presents at a relatively older age and is rarely reported among SCD patients. In this review, we highlight the epidemiological association of SCD-RA and discuss the underlying common pathogenetic mechanisms, such as endothelial dysfunction, the role of inflammatory cytokines and oxidative stress. We also point to the difficulties in ascertaining the clinical diagnosis of RA in SCD patients. Finally, we provide rationale for therapeutic options available for RA and the challenges in the management of these patients with agents that are known to increase the risk of infection and immunosuppression such as steroids, disease modifying anti-rheumatic drugs and biologics.