Changes In Levels Of Proinflammatory Cytokines Research Articles

Histological Improvement and Cytokine Levels Reduction in Patients with Oral Lichen Planus after Photobiomodulation Therapy.

Background: Oral lichen planus (OLP) is a mucocutaneous disease associated with the formation of symptomatic lesions in the mouth that are often refractory to treatment. An as-yet-unknown antigen triggers an inflammatory reaction in which various immune and non-immune cells release multiple cytokines that contribute to disease progression. The ability of photobiomodulation (PBM) to reduce the symptoms and signs of the disease has been shown, but little is known about its molecular and cellular effects. The aim of this study was to evaluate changes in pro-inflammatory cytokine levels and in histological findings in OLP patients treated with photobiomodulation therapy. Methods: Twenty OLP patients underwent PBM with diode laser (810 nm), (0.50 W, 30 s, 1.2 J/cm2), 3 times weekly for a month. Pain level and clinical scores of lesions were recorded before and after therapy. Salivary levels of IL-1β, IL-6, and TNF-α in OLP patients were measured before and after PBM and compared with those of 10 healthy controls. Biopsies were taken at the beginning and end of treatment to assess pathomorphological changes. Results: PBM significantly reduced the level of pain and clinical scores of the lesions. Salivary levels of IL-1β, IL-6, and TNF-α in OLP patients were significantly higher compared to those in healthy controls and decreased after therapy. 60% of the post-treatment OLP biopsies demonstrated histological improvement, characterized by inflammatory infiltrate reduction (50%), epithelial hyperplasia reduction (30%), epithelial thickening (15%), or epidermal-dermal attachment repair (5%). Conclusion: The effectiveness of PBM therapy in OLP patients was confirmed at the clinical, molecular, and histomorphological levels.

Effects of melatonin on disease improvement and serum levels of pro-inflammatory cytokines in patients with non-atypical endometrial hyperplasia

ABSTRACT Background Endometrial hyperplasia (EH), an abnormal proliferation of the endometrial cells, is considered as one of the most common causes of abnormal uterine bleeding. Previous studies have reported that melatonin plays a fundamental role in disease treatment. This study aimed the comparison of the effects of progesterone, as the most common therapeutic approach, and melatonin with progesterone alone in improvement of non-atypical endometrial hyperplasia (NEH) and changes in pro-inflammatory cytokine levels. Methods Study population consisted of 40 patients with NEH. Patients were divided into two groups, including 20 subjects treated with melatonin and progesterone and 20 individuals treated with progesterone alone. The blood and endometrial sampling was performed from participants before and after a three-month treatment. The histological examination was microscopically done. The serum levels of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were measured using ELISA. Results There was no significant difference in the diabetes status and mean age between patients treated with progesterone and melatonin and those treated with progesterone alone. The improvement rate in the EH was significantly higher in individuals treated with progesterone and melatonin than those treated with progesterone alone (p < 0.05). Additionally, the patients treated with progesterone and melatonin showed significant increases inIFN-γ and TNF-αlevels compared to the control group (p < 0.001-P < 0.05). Conclusion Melatonin supplementation has a beneficial effect in the treatment of EH due perhaps to enhance the level of IFN-γ and TNF-α.

Negative impact on bone homeostasis in postmenopausal women with non-metastatic breast cancer during cytotoxic chemotherapy.

The burden and mechanisms of endocrine therapy-related bone loss are well known, while there are limited data on chemotherapy-induced bone resorption. The study aimed to evaluate the effect of cytotoxic chemotherapy on bone homeostasis among postmenopausal women with non-metastatic breast cancer. Early and locally advanced postmenopausal non-metastatic breast cancer patients aged 45 to 65 planned for three cycles of anthracycline and four cycles of taxane chemotherapy administered along with dexamethasone (cumulative dose-256mg) as an antiemetic from June 2018 to December 2021 were included. Bone mineral density (BMD), bone turnover markers, calciotropic hormones, pro-inflammatory cytokines, oxidative stress, and total antioxidant levels (TAS) were measured. We recruited 109 patients, with early 34 (31.2%) and locally advanced breast cancer 75 (68.8%) with median age 53 (45-65) years. There was a significant decrease in the % BMD at the lumbar spine, neck of the femur, and total hip post-chemotherapy. There was a significant increase in serum C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels post-chemotherapy. PINP/CTX ratio significantly decreased post-chemotherapy. Serum 25-OH vitamin D was significantly reduced with a compensatory increase in plasma iPTH levels. The change in CTX, PINP/CTX ratio, 25-OH vitamin D, iPTH, and oxidative stress index was more pronounced during anthracycline as taxane chemotherapy. There were no significant changes in pro-inflammatory cytokine levels. Chemotherapy and dexamethasone as antiemetic resulted in significant bone loss, as evidenced by bone turnover markers. Further studies are required to understand the mechanism of chemotherapy-induced bone loss and the need for bone-strengthening agents during chemotherapy.

Acetylcorynoline inhibits microglia activation by regulating EGFR/MAPK signaling to promote functional recovery of injured mouse spinal cord

To investigate the effect of acetylcorynoline (Ace) for promoting functional recovery of injured spinal cord in rats and explore the underlying mechanism. Rat models of spinal cord injury (SCI) were treated with intraperitoneal injection of different concentrations of Ace, with the sham-operated rats as the control group. After the treatment, the changes in motor function of the rats and the area of spinal cord injury were assessed with BBB score and HE staining, and the changes in pro-inflammatory cytokine levels and microglial activation were determined using PCR, ELISA and immunofluorescence staining. In a lipopolysaccharide (LPS)-treated BV2 cell model, the effects of different concentrations of Ace or DMSO on microglial activation and inflammatory cytokine production were observed. Network pharmacology analysis was performed to predict the target protein and signaling mechanism that mediated the inhibitory effect of Ace on microglia activation, and AutoDock software was used for molecular docking between Ace and the target protein. A signaling pathway blocker (Osimertinib) was used to verify the signaling mechanism in rat models of SCI and LPS-treated BV2 cell model. In rat models of SCI, Ace treatment significantly increased the BBB score, reduced the area of spinal cord injury, and lowered the number of activated microglia cells and the levels of pro-inflammatory cytokines (P < 0.05). The cell experiments showed that Ace treatment significantly lower the level of cell activation and the production of inflammatory cytokines in LPS-treated BV2 cells (P < 0.05). Network pharmacology analysis suggested that EGFR was the main target of Ace, and they bound to each other via hydrogen bonds as shown by molecular docking. Western blotting confirmed that Ace inhibited the activation of the EGFR/MAPK signaling pathway in injured mouse spinal cord tissue and in LPS-treated BV2 cells, and its inhibitory effect was comparable to that of Osimertinib. In rat models of SCI, treatment with Ace can inhibit microglia-mediated inflammatory response by regulating the EGFR/MAPK pathway, thus promoting tissue repair and motor function recovery.

Sex‐related differences in how hyperactive platelets exacerbate the cytokine storm in the peritoneal cavity during intra‐abdominal sepsis

Intra‐abdominal sepsis, a complex clinical syndrome resulting from a serious infection, is a major healthcare problem associated with high morbidity and mortality. Inflammatory cytokine levels in the peritoneal cavity (PC) are much higher than in blood, and the enhanced release of these mediators is a key participant to the deleterious effects of sepsis. Platelets are well‐known for their role in modulating proinflammatory cytokine secretion. We have previously shown that in vivo blockade of P2Y12 signaling, an important regulator for platelet secretion, resulted in lower inflammatory cytokines in the blood. We hypothesize that proinflammatory cytokine levels in the peritoneal cavity will be elevated in a murine model of sepsis. To this end, male and female mice underwent a cecal ligation and puncture (CLP) procedure to induce sepsis and were treated with ticagrelor to block P2Y12 signaling. Peritoneal cavity cells and fluid (PCF) were collected 24 hrs post‐surgery to measure changes in proinflammatory cytokine levels and immune cell interactions. Our data show that during CLP‐induced sepsis, PCF exhibited very low platelet counts and platelet‐immune cell aggregates compared to sham‐treated mice irrespective of sex (*p £ 0.05, n=4). Surprisingly, despite low platelet numbers, soluble p‐selectin and PF‐4 levels were elevated, indicative of platelet secretion. Moreover, P2Y12 antagonist treatment significantly decreased platelet markers and immune cell aggregates in PCF from male but not female mice (*p £ 0.05, n=5). In conclusion, intercellular communication mediated through systemic platelet activation influences the peritoneal cavity during intra‐abdominal sepsis, even in the absence of platelets locally in a sex‐related manner.Moreover, P2Y12 antagonist treatment significantly decreased platelet markers and immune cell aggregates in PCF from male but not female mice. In conclusion, intercellular communication mediated through systemic platelet activation influences the peritoneal cavity during intra‐abdominal sepsis, even in the absence of platelets locally in a sex‐related manner.

MSCs derived from amniotic fluid and umbilical cord require different administration schemes and exert different curative effects on different tissues in rats with CLP-induced sepsis

BackgroundMesenchymal stem cells (MSCs) are derived from multiple tissues, including amniotic fluid (AF-MSCs) and the umbilical cord (UC-MSCs). Although the therapeutic effect of MSCs on sepsis is already known, researchers have not determined whether the cells from different sources require different therapeutic schedules or exert different curative effects. We assessed the biofunction of the administration of AF-MSCs and UC-MSCs in rats with caecal ligation and puncture (CLP)-induced sepsis.MethodsCLP was used to establish a disease model of sepsis in rats, and intravenous tail vein administration of AF-MSCs and UC-MSCs was performed to treat sepsis at 6 h after CLP. Two phases of animal experiments were implemented using MSCs harvested in saline with or without filtration. The curative effect was measured by determining the survival rate. Further effects were assessed by measuring proinflammatory cytokine levels, the plasma coagulation index, tissue histology and the pathology of the lung, liver and kidney.ResultsWe generated rats with medium-grade sepsis with a 30–40% survival rate to study the curative effects of AF-MSCs and UC-MSCs. MSCs reversed CLP-induced changes in proinflammatory cytokine levels and coagulation activation. MSCs ameliorated CLP-induced histological and pathological changes in the lung, liver and kidney. AF-MSCs and UC-MSCs functioned differently in different tissues; UC-MSCs performed well in reducing the upregulation of inflammatory cytokine levels in the lungs and inhibiting the inflammatory cell infiltration into the liver capsule, while AF-MSCs performed well in inhibiting cell death in the kidneys and reducing the plasma blood urea nitrogen (BUN) level, an indicator of renal function.ConclusionsOur studies suggest the safety and efficacy of AF-MSCs and UC-MSCs in the treatment of CLP-induced sepsis in rats and show that the cells potentially exert different curative effects on the main sepsis-affected tissues.

Emotional Traumatic Brain Injury.

The definition of traumatic brain injury (TBI) has expanded to include mild TBI and postconcussive syndrome. This evolution has resulted in difficulty disentangling the physical trauma of mild TBI from the emotional trauma of posttraumatic stress disorder (PTSD). Advances in stress neurobiology and knowledge of brain injury at the macroscopic, microscopic, biochemical, and molecular levels call for a redefinition of TBI that encompasses both physical and emotional TBI. Conceptualizing a spectrum of TBI with both physical and emotional causation resolves the irreconcilable tangle between diagnostic categories and acknowledges overlapping forms of brain injury and shared systemic effects due to hormonal and inflammatory mediators. Recognizing emotional TBI shifts the interpretation of emotional trauma from a confound to a comorbid, related cause of brain injury. The mechanism of emotional TBI includes the intricate actions of stress hormones on diverse brain functions due to changes in synaptic plasticity, where chronically elevated hormone levels reduce neurogenesis, resulting in dendritic atrophy and impaired cognition. The overlapping effects of physical and emotional trauma are seen in neuropathology (ie, reduction of hippocampal volume in TBI and PTSD); fMRI (similar regional activations in physical and emotional pain); and systemic sequelae, including changes in proinflammatory cytokine levels and immune cell function. Accumulating evidence favors a change in the definition of TBI to encompass emotional TBI. The definition of TBI will be strengthened by the inclusion of both physical and emotional trauma that result in diverse and overlapping forms of brain injury with sequelae for physical and mental health.

Hesperetin ameliorates lipopolysaccharide-induced acute lung injury via the miR-410/SOX18 axis.

Hesperetin (Hesp), a dihydroflavone, has a wide range of pharmacological activities, including antioxidant, anti-inflammatory, and antitumor effects, as well as cardiovascular protection. It also has protective effects against acute lung injury (ALI); however, the exact mechanism remains unclear. In the present study, the protective effects and mechanism of Hesp in the lungs were investigated. Hematoxylin and eosin staining was used to examine pathological changes in the lungs. Enzyme-linked immunosorbent assay was used to detect proinflammatory cytokine levels. In addition, reverse transcription-quantitative polymerase chain reaction and Western blot analysis were used to observe the transcription and translation changes in the related genes, respectively. The results indicate that Hesp not only improves histopathological changes in the lungs but decreases the wet/dry ratio. In addition, total cell counts and the number of neutrophils and macrophages were lower in the bronchoalveolar fluid after Hesp treatment, consistent with the change in proinflammatory cytokine levels. MicroRNA-410 (miR-410) levels were significantly lower in the lung tissues of ALI mice and were reversed after Hesp treatment. Furthermore, miR-410 overexpression due to injection with agomiR-410 produced similar protective effects as Hesp. However, blocking miR-410 inhibited the protective effects of Hesp in the lungs of ALI mice. In addition, miR-410 has been shown to target the inhibition of sex determining region Y-box 18 (SOX18), indicating that Hesp might alleviate inflammatory secretion by blocking the miR-410/SOX18 axis. Thus, Hesp might be a potential agent for the treatment of ALI.

Early changes in pro-inflammatory cytokine levels in neonates with encephalopathy are associated with remote epilepsy.

BackgroundNeonatal seizures are associated with adverse neurologic sequelae including epilepsy in childhood. Here, we aim to determine whether levels of cytokines in neonates with brain injury are associated with acute symptomatic seizures or remote epilepsy.MethodsThis is a cohort study of term newborns with encephalopathy at UCSF between 10/1993 and 1/2000 who had dried blood spots. Maternal, perinatal/postnatal, neuroimaging, and epilepsy variables were abstracted by chart review. Logistic regression was used to compare levels of cytokines with acute seizures and the development of epilepsy.ResultsIn a cohort of 26 newborns with neonatal encephalopathy at risk for hypoxic ischemic encephalopathy with blood spots for analysis, diffuse alterations in both pro- and anti-inflammatory cytokine levels were observed between those with (11/28, 39%) and without acute symptomatic seizures. Seventeen of the 26 (63%) patients had more than two years of follow-up and 4/17 (24%) developed epilepsy. Higher levels of pro-inflammatory cytokines IL-6 and TNF-α, within the IL-1β pathway were significantly associated with epilepsy.ConclusionsElevations in pro-inflammatory cytokines in the IL-1β pathway were associated with later onset of epilepsy. Larger cohort studies are needed to confirm the predictive value of these circulating biomarkers.

Evaluation of selective and non-selective cyclooxygenase inhibitors on sulfur mustard-induced pro-inflammatory cytokine formation in normal human epidermal keratinocytes

Sulfur mustard (SM) is a highly toxic chemical warfare agent, which produces blisters after skin contact. Treatment of SM-induced adverse health effects, such as cutaneous blistering, ulceration, and inflammation remains a challenging task. Antidotes or specific therapeutic measures are lacking. Some drugs (e.g. cyclooxygenase (COX) inhibitors) exhibited beneficial effects after SM poisoning in vivo. However, in vitro studies that evaluate and compare the potency of COX inhibitors are missing. In the presented study, non-specific (acetylsalicylic acid, ibuprofen, diclofenac, indomethacin, and piroxicam), COX-2-specific (celecoxib and parecoxib) inhibitors and COX-independent drugs (paracetamol and tofacitinib) were compared regarding anti-inflammatory and cytoprotective effects after SM exposure in post-exposure treatment settings. Normal human epidermal keratinocytes (NHEK) were used as a surrogate model. Prostaglandin E2 (PGE2) formation, a direct indicator for COX activity, was determined by ELISA. Changes in pro-inflammatory cytokine levels after SM exposures were assessed by quantitative determination of 27 inflammatory cytokines using a multiplex method. Cytotoxicity was determined using an XTT viability assay. The results demonstrated that SM highly increased PGE2 production and release of pro-inflammatory cytokines, predominantly IL-6, IL-8 and TNF-α. In general, all COX inhibitors and paracetamol were able to reduce the PGE2 formation, while tofacitinib, an inhibitor of Janus kinase, had no influence on PGE2 levels. In addition, IL-6, IL-8, and TNF-α formation were also inhibited, but sometimes independently of PGE2. The COX-2 specific celecoxib was identified as the most potent drug to reduce IL-6, IL-8 and TNF-α formation after SM exposures in vitro. However, cell viability was not improved significantly by any of the investigated drugs in our experiments.

The effect of retinyl-palmitate on the level of pro and anti-inflammatory cytokines in multiple sclerosis patients: A randomized double blind clinical trial

ObjectiveMultiple sclerosis (MS) is an inflammatory and autoimmune disease associated with the imbalance of cytokines secreted from CD4+ T cells. Studies have shown that vitamin A and its active derivatives are able to modulate the immune system in MS patients. The aim of the present study was to investigate the effect of supplementation of retinyl palmitate (RP), the dietary form of vitamin A, on pro- and anti-inflammatory cytokines in the plasma and supernatants of cultured peripheral blood mononuclear cells (PBMCs) of MS patients. Patients and methodsThirty-six relapsing-remitting MS patients were enrolled in this double-blind randomized clinical trial. Participants received one capsule of 25,000 IU RP or a placebo per day for six months. Blood samples were taken before and after intervention. After intervention, the PBMCs were isolated and cultured. The levels of pro- and anti-inflammatory cytokines in the plasma and supernatant of cells stimulated with myelin oligodendrocyte glycoprotein, phytohemagglutinin or vehicle (media) were determined. The sample t-test and Mann Whitney U test were used to compare data between groups. ResultsThe changes in pro-inflammatory cytokine levels (IL-1β, TNF-α, IFN- γ, IL-2, IL-6, and IL-17) in the serum and supernatant of MS patients were not significant (p > 0.05). There were also no significant changes in the levels of anti-inflammatory cytokines (IL-10, IL-13, IL-4, and TGF-β) (p > 0.05). ConclusionUnexpectedly, this study found no significant changes in cytokine levels after six months of RP supplementation in MS patients. The results of other studies by our team have shown significant changes in the gene expression of the cytokines in response to RP supplements. Therefore, we recommend that periodic follow-up of RP supplementation may be needed to reveal changes in the level of the cytokines in the plasma and PBMCs and to clarify the real effect of RP on the immune factor levels in the serum of MS patients.

Changes in pro-inflammatory cytokine levels and late-life depression: A two year population based longitudinal study

Longitudinal associations of cytokine levels with depression are unclear. This study aimed to investigate cross-sectional and prospective associations between five serum pro-inflammatory cytokine levels and late-life depression. 732 Korean people aged 65+ were evaluated at baseline. Of 631 without depression (Geriatric Mental State schedule) at baseline, 521 (83%) were followed over a 2 year period and incident depression was ascertained. Serum tumor necrosis factor-α, interleukin (IL)-1α, IL-1β, IL-6, and IL-8 levels were assayed at both baseline and follow-up. Associations between cytokine levels and depressive status were evaluated using linear regression models, considering potential covariates (demographics, cognitive function, disability, lifestyle factors, and vascular risk factors) and applying Bonferroni corrections. Prevalent depression at baseline was significantly associated with higher contemporaneous levels of IL-1β and IL-8, independent of relevant covariates and after applying Bonferroni corrections. In the analyses of the five cytokine levels in combination, independent associations were found between prevalent depression and increased numbers of cytokines at higher levels at baseline. Incident depression was significantly associated with increases in IL-1β, IL-6, and IL-8 levels during the follow-up independent of relevant covariates and after applying Bonferroni corrections. In combination analyses, incident depression was independently associated with higher numbers of cytokines showing increasing levels over the same follow-up period. However, incident depression was not predicted by higher baseline pro-inflammatory cytokine levels in any analysis. Our findings suggest that depression might affect serum cytokines alterations and lead to inflammatory processes in late-life.

Effects of Tourniquet Use during Total Knee Arthroplasty on Global Cytokine Changes Associated with Ischemia Reperfusion Injury

PURPOSE: The use of tourniquets during total knee arthroplasties (TKA) has been debated given the possibility that prolonged application of a tourniquet may result in ischemia-reperfusion injury (IRI), potentially contributing to post-operative muscle atrophy. The goal of this study was to elucidate the influence that tourniquet use may have on the induction of IRI in muscle tissue following TKA surgeries. We hypothesized that tourniquet use during TKA causes larger global increases in pro-inflammatory cytokines, indicating the occurrence of IRI. METHODS: 50 patients undergoing TKA surgeries were separated into 3 groups: no tourniquet (NoT; n=17), operative tourniquet (OT; n=15), and tourniquet during implant cementation (TDC; n=18). Induction of IRI was evaluated by measuring changes in fifteen cytokines present in blood samples collected from an antecubital vein immediately before and after surgery. Pre- to post- surgery changes in cytokine concentrations were compared between groups. RESULTS: Compared to immediately before surgery, cytokine levels generally decreased after surgery in the NoT and OT groups, but increased in the TDC group. Despite these differences, pre- to post- operation changes in IL-1β, IL-10, IFNY, IL-4, IL-5, IL-7, IL-8, Eotaxin, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, and TNFα concentrations were not significantly different between groups. However, significant differences were found for IL-12, a pro-inflammatory cytokine (p=0.01). After surgery, IL-12 concentrations decreased in the NoT (pre: 72.8 ± 89.8 pg/mL, post: 41.3 ± 28.6 pg/mL) and OT (pre: 92.1 ± 142.2 pg/mL, post: 82.9 ± 167.4 pg/mL) groups, and increased in the TDC group (pre: 52.0 ± 85.1 pg/mL, post: 63.0 ± 116.7 pg/mL). However, Cohen’s d effect sizes between groups were small (NoT vs OT = 0.08; NoT vs TDC = 0.12; OT vs TDC = 0.18). CONCLUSIONS: Using global changes in pro-inflammatory cytokine levels as an indicator of IRI, these data suggest that the use of a tourniquet does not significantly contribute to induction of IRI in TKA surgeries. However, additional studies comparing local plasma cytokine changes near the tourniquet site and utilizing larger sample sizes are necessary to determine if tourniquets should be used in TKA without inducing IRI.

Supplementation with nutrients modulating insulin-like growth factor-1 negatively correlated with changes in the levels of pro-inflammatory cytokines in community-dwelling elderly people at risk of undernutrition.

Suboptimal nutrition accompanied by chronic low-grade increases in circulating cytokine levels is more common in elderly people. We explored the improvement in nutritional status, especially in the level of insulin-like growth factor-1 (IGF-1) and its relationship with changes in circulating cytokine levels, after providing extra protein and energy content to community-dwelling older adults at risk of undernutrition. Sixty nondiabetic subjects, aged ≥65years and living independently in a community for elderly people, with a serum pre-albumin level ≤30mg dL-1 and a body mass index <25kg m-2 , were recruited. The subjects were followed for a 2-week pre-intervention period, during which they maintained routine dietary habits. This was followed by an intervention period, during which they received oral nutritional supplementation for 2weeks. Following 2weeks of intervention, there were significant increases in total lymphocyte count (TLC) and insulin-like growth factor (IGF)-1, pre-albumin and transferrin compared to baseline. Body weight and mid-arm circumference significantly increased without alteration of tricep skinfold thickness at the end of the intervention. There was a significant reduction in interleukin (IL)-6 levels and a trend toward a decrease in the tumor necrosis factor (TNF)-α levels. At baseline, age was negatively correlated with IGF-1 levels and positively correlated with IL-6 and TNF-α levels. The change (▵, from baseline) in IGF-1 level was positively correlated with age and negatively correlated with ▵IL-6 and ▵TNF-α. A 2-week intervention with oral nutritional supplementation improved nutritional status and decreased circulating cytokine levels. Specifically, ▵IGF-1 was negatively correlated with changes in pro-inflammatory cytokine levels in community-dwelling elderly people at risk of undernutrition. (Clinicaltrials.gov: NCT02656186).

Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia.

Exercise intolerance, as evidenced by a worsening of pain, fatigue, and stiffness after novel exertion, is a key feature of fibromyalgia (FM). In this pilot study, we investigate whether; insufficient muscle repair processes and impaired anti-inflammatory mechanisms result in an exaggerated pro-inflammatory cytokine response to exhaustive exercise, and consequently a worsening of muscle pain, stiffness and fatigue in the days post-exercise. We measured changes in muscle pain and tenderness, fatigue, stiffness, and serum levels of neuroendocrine and inflammatory cytokine markers in 20 women with FM and 16 healthy controls (HCs) before and after exhaustive treadmill exercise. Compared to HCs, FM participants failed to mount the expected anti-inflammatory response to exercise and experienced a worsening of symptoms post-exercise. However, changes in post-exertional symptoms were not mediated by post-exertional changes in pro-inflammatory cytokine levels. Implications of these findings are discussed.

Pulmonary Immune Responses to Aspergillus Fumigatus in Rats

ObjectiveTo evaluate immunologic mechanisms underlying Aspergillus fumigatus pulmonary infections in immunocompetent Dark Agouti (DA) and Albino Oxford (AO) rats recognized as being susceptible to some inflammatory diseases in different manners. MethodsLung fungal burden (quantitative colony forming units, CFU, assay), leukocyte infiltration (histology, cell composition) and their function (phagocytosis, oxidative activity, CD11b adhesion molecule expression) and cytokine interferon-γ (IFN-γ) and interleukin-17 and −4 (IL-17 and IL-4) lung content were evaluated following infection (intratracheally, 1×107 conidia). ResultsSlower reduction of fungal burden was observed in AO rats in comparison with that in DA rats, which was coincided with less intense histologically evident lung cell infiltration and leukocyte recovery as well as lower level of most of the their activities including intracellular myeloperoxidase activity, the capacity of nitroblue tetrazolium salt reduction and CD11b adhesion molecule expression (except for phagocytosis of conidia) in these rats. Differential patterns of changes in proinflammatory cytokine levels (unchanged levels of IFN-γ and transient increase of IL-17 in AO rats vs continuous increase of both cytokines in DA rats) and unchanged levels of IL-4 were observed. ConclusionGenetically-based differences in the pattern of antifungal lung leukocyte activities and cytokine milieu, associated with differential efficiency of fungal elimination might be useful in the future use of rat models in studies of pulmonary aspergillosis.

Vaccination induced changes in pro-inflammatory cytokine levels as an early putative biomarker for cognitive improvement in a transgenic mouse model for Alzheimer disease

Several pieces of experimental evidence suggest that administration of anti-β amyloid (Aβ) vaccines, passive anti-Aβ antibodies or anti-inflammatory drugs can reduce Aβ deposition as well as associated cognitive/behavioral deficits in an Alzheimer disease (AD) transgenic (Tg) mouse model and, as such, may have some efficacy in human AD patients as well. In the investigation reported here an Aβ 1–42 peptide vaccine was administered to 16-month old APP+PS1 transgenic (Tg) mice in which Aβ deposition, cognitive memory deficits as well as levels of several pro-inflammatory cytokines were measured in response to the vaccination regimen. After vaccination, the anti-Aβ 1–42 antibody-producing mice demonstrated a significant reduction in the sera levels of 4 pro-inflammatory cytokines (TNF-α, IL-6, IL-1 α, and IL-12). Importantly, reductions in the cytokine levels of TNF-α and IL-6 were correlated with cognitive/behavioral improvement in the Tg mice. However, no differences in cerebral Aβ deposition in these mice were noted among the different control and experimental groups, i.e., Aβ 1–42 peptide vaccinated, control peptide vaccinated, or non-vaccinated mice. However, decreased levels of pro-inflammatory cytokines as well as improved cognitive performance were noted in mice vaccinated with the control peptide as well as those immunized with the Aβ 1-42 peptide. These findings suggest that reduction in pro-inflammatory cytokine levels in these mice may be utilized as an early biomarker for vaccination/treatment induced amelioration of cognitive deficits and are independent of Aβ deposition and, interestingly, antigen specific Aβ 1–42 vaccination. Since cytokine changes are typically related to T cell activation, the results imply that T cell regulation may have an important role in vaccination or other immunotherapeutic strategies in an AD mouse model and potentially in AD patients. Overall, these cytokine changes may serve as a predictive marker for AD development and progression as well as having potential therapeutic implications.

Proinflammatory cytokine levels in patients with conversion disorder.

It was aimed to evaluate the relationship between proinflammatory cytokine levels and conversion disorder both commonly known as stress regulated. Baseline proinflammatory cytokine levels-[Tumour necrosis factor alpha (TNF-α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6)]-were evaluated with enzyme-linked immunosorbent assay in 35 conversion disorder patients and 30 healthy controls. Possible changes in proinflammatory cytokine levels were evaluated again, after their acute phase in conversion disorder patients. Statistically significant decreased serum TNF-α levels were obtained in acute phase of conversion disorder. Those levels increased after acute conversion phase. There were no statistically significant difference observed between groups in serum IL-1β and (IL-6) levels. Stress associated with conversion disorder may suppress immune function in acute conversion phase and may have diagnostic and therapeutic value.

Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice

Sex is an important factor in the response to ischemic insults in both the laboratory and the clinic. Inflammation and cell death are points where sex-specific pathways diverge in stroke, and serum estrogen level status affect the response to inflammation. The cytokine macrophage migration inhibitory factor (MIF) is detrimental in experimental stroke models in male animals. However MIF is known to have sex-specific actions on inflammation and wound healing. The role of MIF in the ischemic female brain has not been evaluated. A transient middle cerebral artery occlusion (MCAO/90min) model was used to induce stroke in male, intact female, and ovariectomized female wildtype (WT) and MIF knockout (KO) mice. Infarct size was quantified 72h after stroke. Protein and cytokine levels were assessed post stroke. Female MIF KO mice had significantly larger strokes compared to WT females (mean hemispheric infarct±SEM: 63%±2% versus 29%±3%; n=8; p<0.05). Ovariectomized female MIF KO mice also had larger infarcts than ovariectomized WT littermates (70%±3% versus 47%±4%; n=11; p<0.05). In males, however, infarct size was equivalent between MIF KO and WT mice (63%±2% versus 67%±3%; n=9; p=0.25). There were no significant differences in cytokine levels at 6h post-infarct between mice of either genotype in brain. MIF KO females displayed more microglial activation (ionized calcium binding adaptor molecule 1 (Iba1) immunofluorescence) after stroke than did WT mice or MIF KO males. The larger infarcts in MIF KO females were associated with an early increase in mitochondrial localization of Jun activation domain-binding protein 1 (JAB1). Loss of MIF exacerbated injury in the female brain after experimental stroke, which was independent of changes in pro-inflammatory cytokine levels. This response is sex-specific, and is in part independent of physiological serum levels of estrogen.

Dietary Phosphatidylcholine Supplementation Attenuates Inflammatory Mucosal Damage in a Rat Model of Experimental Colitis

This study was designed to follow the time course of inflammatory activation in a rodent model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. We hypothesized that oral phosphatidylcholine (PC) pretreatment regimens may influence leukocyte-mediated microcirculatory reactions in this condition. In series I, Wistar rats were monitored 1 day after colitis induction (n = 24), and in series II (n = 24) on day 6 following a TNBS enema. The PC-pretreated animals received a 2% PC-enriched diet for 6 days before the TNBS enema (series I), or for 3 days before and 3 days after TNBS treatment (series II). The macrohemodynamics, serosal microcirculation (visualized by intravital videomicroscopy), colonic xanthine oxidoreductase, myeloperoxidase and nitric oxide end products, and changes in proinflammatory cytokine levels in plasma were measured. The mucosal structural injury was monitored in vivo by means of confocal laser scanning endomicroscopy. The TNBS enema induced a systemic hyperdynamic circulatory reaction with increased serosal capillary blood flow and significantly elevated colonic inflammatory enzyme activities, levels of nitric oxide production, and cytokine concentrations. Acute colitis caused disruption of the capillary network, whereas the morphologic damage was less severe in series II. The PC pretreatment protocols led to significant decreases in the serosal hyperemic reaction, the cytokine levels, and the inflammatory enzyme activities. The objective signs of tissue damage were reduced in both series, and the number of mucus-producing goblet cells in the resolving phase of colitis was increased. Dietary PC efficiently decreases the cytokine-mediated progression of inflammatory events and preserves the microvascular structure in the large intestine.