Cytokines In Animal Models Research Articles

The Neuroprotective Effects of Agmatine on Parkinson's Disease: Focus on Oxidative Stress, Inflammation and Molecular Mechanisms.

Agmatine (AGM), a naturally occurring polyamine derived from L-arginine, has shown significant potential for neuroprotection in Parkinson's Disease (PD) due to its multifaceted biological activities, including antioxidant, anti-inflammatory, and anti-apoptotic effects. This review explores the therapeutic potential of AGM in treating PD, focusing on its neuroprotective mechanisms and evidence from preclinical studies. AGM has been demonstrated to mitigate the neurotoxic effects of rotenone (ROT) by improving motor function, reducing oxidative stress markers, and decreasing levels of pro-inflammatory cytokines in animal models. Additionally, AGM protects against the loss of TH + neurons, crucial for dopamine synthesis. The neuroprotective properties of AGM are attributed to its ability to modulate several key pathways implicated in PD pathogenesis, such as inhibition of NMDA receptors, activation of Nrf2, and suppression of the HMGB1/ RAGE/ TLR4/ MyD88/ NF-κB signaling cascade. Furthermore, the potential of agmatine to promote neurorestoration is highlighted by its role in enhancing neuroplasticity elements such as CREB, BDNF, and ERK1/2. This review highlights agmatine's promising therapeutic potential in PD management, suggesting that it could offer both symptomatic relief and neuroprotective benefits, thereby modifying the disease course and improving the quality of life for patients. Further research is warranted to translate these preclinical findings into clinical applications.

Systemic cytokines inhibition with Imp7 siRNA nanoparticle ameliorates gut injury in a mouse model of ventilator-induced lung injury

Mechanical ventilation (MV) may negatively affect the lungs and cause the release of inflammatory mediators, resulting in extra-pulmonary organ dysfunction. Studies have revealed systemically elevated levels of proinflammatory cytokines in animal models of ventilator-induced lung injury (VILI); however, whether these cytokines have an effect on gut injury and the mechanisms involved remain unknown. In this study, VILI was generated in mice with high tidal volume mechanical ventilation (20 ml/kg). Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 concentrations in serum and gut measured by ELISA showed significant elevation in the VILI mice. Significant increases in gut injury and PANoptosis were observed in the VILI mice, which were positively correlated with the serum levels of TNF-α, IL-1β, and IL-6. The VILI mice displayed intestinal barrier defects, decreased expressions of occludin and zonula occludin-1 (ZO-1), and increased expression of claudin-2 and the activation of myosin light chain (MLC). Importantly, intratracheal administration of Imp7 siRNA nanoparticle effectively inhibited cytokines production and protected mice from VILI-induced gut injury. These data provide evidence of systemic cytokines contributing to gut injury following VILI and highlight the possibility of targeting cytokines inhibition via Imp7 siRNA nanoparticle as a potential therapeutic intervention for alleviating gut injury following VILI.

Effect of electroacupuncture on serum inflammatory cytokines in animal models with rheumatoid arthritis: A systematic review and meta-analysis

Rheumatoid arthritis (RA) is an autoimmune disease. Electroacupuncture (EA) as an alternative therapy shows particular advantages in RA treatment. However, the therapeutic mechanism of EA in RA is unclear. The meta-analysis aimed to investigate the effect and the mechanism of EA on serum inflammatory cytokines in RA animal models. We searched nine databases from inception to July 14, 2022, and extracted serum inflammatory cytokines as outcome indicators. SYRCLE risk of bias tool was used to evaluate the quality of studies. The meta-analysis used Review Manager 5.3 and Stata 12.0 software. 4478 studies were identified in the initial search, and 16 studies were included. The results showed that, compared with the control group, EA treatment significantly reduced the level of IL-1 (SMD = -3.70, 95%CI: -6.55 to -0.85), IL-6 (SMD = -1.96, 95%CI: -3.81 to -0.11), IL-17 (SMD = -2.65, 95%CI: -3.29 to -2.02), IL-23 (MD = -95.57, 95%CI: -162.63 to -28.51), IL-1β (SMD = -3.13, 95%CI: -4.31 to -1.96), and TNF-α (SMD = -2.52, 95%CI: -3.26 to -1.78). Besides, EA increased IL-2 (MD = 19.98, 95%CI: 11.30 to 28.65). However, there was no significant difference in the IFN-r, IL-4, and IL-10 levels. Egger's test and Begg's test were p = 0.001. The meta-analysis demonstrated that EA was effective and had a significant function of relieving inflammation and immune regulation in RA animal models. Due to the potential publication bias and low quality of evidence, higher quality and well-designed animal studies are needed to confirm the results.

Monocyte-derived macrophages: The supplements of hepatic macrophage in Echinococcus multilocularis infected mice.

BackgroundAlveolar echinococcosis is a potentially lethal zoonosis caused by the cestode Echinococcus multilocularis. This study is to investigate the dynamic changes of monocytes, macrophages, and related cytokines in animal models of persistent infection of E. multilocularis.MethodsAn infection model was established by intraperitoneal injection of a protoscolex suspension. The pathological changes of liver were observed by HE staining. The percentage of Ly6Chi and Ly6Clo Monocytes in peripheral blood was detected by flow cytometry. The distribution and expression of CX3CL1, CX3CR1, iNOS, CD163, and CD11b in the liver were detected by immunohistochemistry. The mRNA expression of tumor necrosis factor‐α (TNF‐α) and Arg1 in the liver was detected by quantitative reverse transcription polymerase chain reaction. The expression of INF‐γ, interleukin‐17 (IL‐17), IL‐4, and IL‐10 in peripheral blood was detected by enzyme‐linked immunosorbent assay.ResultsHematoxylin‐eosin(HE) staining showed that significant lesions appeared in the later stages of infection in the liver. The proportion of Ly6Chi monocytes in the peripheral blood of the experimental group mice decreased after a brief rise, Ly6Clo monocytes decreased first and then increased. The expression of CX3CL1, CX3CR1, CD11b, CD163, and iNOS in the mice liver of the experimental group was increased. The expression level of TNF‐α and Arg1 mRNA in the liver of the experimental group mice increased. The expression level of IFN‐γ, IL‐17, IL‐4, and IL‐10 increased with the duration of infection.ConclusionsMonocytes as a supplement to hepatic macrophage, monocytes and kupffer cells may both participate in Th1 and Th2 immune responses by differentiating into M1 or M2 at different stages of E. multilocularis infection.

Effects of ibudilast on central and peripheral markers of inflammation in alcohol use disorder: A randomized clinical trial.

Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro-inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non-treatment-seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2weeks of medication. At study mid-point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline-compounds (Cho), myo-inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast-treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast-treated participants had nominally lower C-reactive protein levels at visit 2 and nominally lower TNF-α/IL-10 ratios, relative to placebo. C-reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro-longitudinal ibudilast treatment may induce peripheral and putative central anti-inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti-inflammatory component to the therapeutic action of ibudilast.

Hedgehog signaling modulates cigarette-induced COPD development.

Hedgehog (Hh) signaling is involved in early embryogenesis and maintains quiescence in the adult lungs. The interruption of Hh signaling may lead to the development of chronic obstructive pulmonary disease (COPD). The current study aimed to assess whether the Hh pathway affects cigarette-induced emphysema and airway inflammation by regulating inflammatory cytokines. C57BL/6J mice were randomized into control, cigarette smoke (CS) or CS + cyclopamine (CSC) groups. Control mice were exposed to normal room air, CS mice were exposed to tobacco smoke and CSC mice were exposed to CS and received cyclopamine treatment. Histopathological examination of lung tissues was performed, and the expression of sonic hedgehog (HH), glioma-associated oncogene homolog 1 (Gli1), hedgehog-interacting protein (HIP) and several inflammatory mediators (intracellular adhesion molecule-1, IL-6, IL-8 and TNF-α) were compared using reverse transcription-quantitative PCR and western blotting. The emphysema of lung tissues by histopathological examination demonstrated partial amelioration in the CSC group compared with that in the CS group. Additionally, expression levels of SHH, Gli1 and inflammatory mediators were significantly higher in the CS group compared with the control group but were significantly decreased in the CSC group. The expression of HIP was decreased in the CS group, but significantly increased in the CSC group. Hh signaling may serve an important role in cigarette-induced emphysema and airway inflammation by regulating inflammatory cytokines in animal models. Therefore, diminishing the activation of the Hh signal may serve as a novel therapeutic strategy for patients suffering from smoking-related COPD.

Euphorbia prostata Exerts Potent Anti-Inflammatory and Anti-Arthritic Activity in Downregulating the Increased Expression of Pro-Inflammatory Cytokines

Background: Euphorbia prostrata constitutes a herbal medication widely used to cure numerous inflammatory diseases occurring either alone or in conjunction with other herbal formulations. The research conducted was devised with the aim of determining the effect of Euphorbia prostrata hydroalcoholic leaf extract on paw swelling, joint destruction, and the formation of inflammation-producing cytokines in animal models of rheumatoid arthritis. Methods: Hydroalcoholic Euphorbia prostrata extract and a reference drug (indomethacin 3mg/kg), were both administered orally on a daily basis at varying doses; low (50 mg/kg), medium (100 mg/kg), and high (200 mg/kg) for a period of 21 days. Other parameters affecting the functional components of bone include joint diameter measurements and histopathological investigations. Immunohistochemical analysis of Interleukin (IL-1, IL-6) and Nuclear Factor(NF-κB)in ankle joint tissue was performed. Results: The research findings indicated that a significant (p<0.05) dose-dependent reduction in inflammation results from the administering of Euphorbia prostrata at varying doses. A 200mg/kg dose of Euphorbia prostrata with a significance of p<0.001 produced a marked reduction in both inflammation and joint dysfunction. It was concluded, therefore, that such a dose attenuates paw oedema and inflammation, while also reversing bone damage through the inhibition of activated pro-inflammatory mediators and, specifically, NF-κB-mediated production of cytokines. Conclusion: The research presented here concludes that Euphorbia prostrata hydroalcoholic extract can be potentially employed in the treatment and management of rheumatoid arthritis since it reduces symptoms of inflammation, inhibits macrophage activity and modulates IL-1, IL-6 and NF-κB.

Phenylmethimazole is a candidate drug for the treatment of severe forms of coronavirus disease 2019 (COVID-19) as well as other virus-induced “cytokines storm”

Severe forms of the Coronavirus disease 2019 (COVID-19) are characterized by an enhanced inflammatory syndrome called “cytokine storm” that produces an aberrant release of high amounts of cytokines, chemokines, and other proinflammatory mediators. The pathogenetic role of the “cytokine storm” has been confirmed by the efficacy of immunosuppressive drugs such as corticosteroids along with antiviral drugs in the treatment of the severe forms of this disease.Phenylmethimazole (C10) is a derivative of methimazole with anti-inflammatory properties. Studies performed both in vitro and in vivo have shown that C10 is able to block the production of multiple cytokines, chemokines, and other proinflammatory molecules involved in the pathogenesis of inflammation. Particularly, C10 is effective in reducing the increased secretion of cytokines in animal models of endotoxic shock. We hypothesize that these effects are not limited to the endotoxic shock, but can also be applied to any disease characterized by the presence of a “cytokine storm”. Therefore, C10 may be a potential drug to be used alternatively or in association with the corticosteroids or other immunosuppressive agents in the severe forms of COVID-19 as well as other viral diseases that induce a “cytokine storm”. Preclinical and clinical studies have to be performed to confirm this hypothesis.

Effect of Moxibustion on Inflammatory Cytokines in Animals with Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Background This study aims to systematically evaluate the effect of moxibustion on the level of inflammatory cytokines in animal models with rheumatoid arthritis (RA) and to provide evidence for the clinical application of moxibustion to the treatment of RA and related basic researches. Methods The databases employed in this study include PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP), SinoMed, and Wanfang Data Information Site. The retrieval time was from the establishment of these databases to March 2020. The reviewers made use of the CAMARADES 10-item checklist to evaluate the quality of each included study. The inflammatory cytokines were considered as the outcome measure. The Revman 5.3 software was used to conduct meta-analysis on the outcome indicators of the studies included. Results A total of 648 articles were retrieved and 18 animal experiments were included in this study. The quality scores of the studies ranged from two to eight with a mean of 5.8. Compared with the effect of the control group, moxibustion reduced the expression of TNF-α (SMD 2.95, 95% CI: 1.99–3.92, P < 0.00001), IL-1β (SMD 4.10, 95% CI: 2.37–5.84, P < 0.00001), IFN-γ (MD 25, 95% CI: 16.17–33.82, P < 0.00001), IL-6 (MD 11.83, 95% CI: 6.22–17.44, P < 0.0001), and IL-17 (MD 99.3, 95% CI: 86.83–111.76, P < 0.00001). At the same time, the level of IL-2 (SMD 8.89, 95% CI: 0.93–16.86, P=0.03), IL-4 (MD 1.79, 95% CI: 0.26–3.32, P=0.02), and IL-10 (MD 5.93, 95% CI: 1.37–10.49, P=0.01) increased after moxibustion treatment. Asymmetric funnel plots indicated that there was publication bias. Conclusion The findings of the present review indicate that moxibustion can protect the synovium of joint in animal models with RA by upregulation of the level of anti-inflammatory cytokines and downregulation of the level of proinflammatory cytokines. Moxibustion has the potential to relieve inflammation of RA.

The relationship between interleukin-6 and functional connectivity in methamphetamine users

Methamphetamine (MA) causes an increase in pro-inflammatory cytokines in animal models and in humans. Resulting activation of microglia and neuro-inflammation could, via effects on reward networks, mediate behavioral characteristics of addiction. We examined the relationship between interleukin-6 (IL-6) and corticolimbic and striatolimbic resting-state functional connectivity (RSFC). Thirty adults diagnosed with MA dependence and 20 control subjects underwent a resting-state functional magnetic resonance imaging (fMRI) scan and gave a blood sample for determination of plasma IL-6 levels. Seed-based RSFC analyses were performed to examine the interactive effect of group and IL-6 on ventral striatal and prefrontal connectivity. Within the MA group, IL-6 levels were positively related to striatolimbic RSFC but negatively related to corticostriatal RSFC. Our findings with IL-6 support the idea that inflammation may at least partly mediate the link among MA use disorder, RSFC, and behavior, possibly via effects on mesolimbic and mesocortical dopaminergic systems.

Inflammation in the pathophysiology of neuropathic pain.

Peripheral nerve injuries and diseases often lead to pain persisting beyond the resolution of damage, indicating an active disease-promoting process, which may result in chronic pain. This is regarded as a maladaptive mechanism resulting from neuroinflammation that originally serves to promote regeneration and healing. Knowledge on these physiological and pathophysiological processes has accumulated over the last few decades and has started to yield potential therapeutic targets. Key players are macrophages, T-lymphocytes, cytokines, and chemokines. In the spinal cord and brain, microglia and astrocytes are involved. Recently, data have been emerging on the regulation of these players. MicroRNAs and other noncoding RNAs have been discussed as potential master switches that may link nerve injury, pain, and inflammation. Clinical disorders most intensely studied in the context of neuroinflammation and pain are the complex regional pain syndrome, polyneuropathies, postherpetic neuralgia, and the fibromyalgia syndrome, in which recently a neuropathic component has been described. Research from several groups has shown an important role of both proinflammatory and anti-inflammatory cytokines in neuropathic and other chronic pain states in humans. There is ample evidence of an analgesic action of anti-inflammatory cytokines in animal models. The interplay of anti-inflammatory cytokines and the nociceptive system provides possibilities and challenges concerning treatment strategies based on this concept.

Expression of aryl hydrocarbon receptor, inflammatory cytokines, and incidence of rheumatoid arthritis in Vietnamese dioxin-exposed people

Many Vietnamese citizens have been and continue to be inadvertently exposed to dioxins and dioxin-like compounds deposited in the country during the Vietnam War. Dioxins may be involved in the pathogenesis of inflammatory diseases in part via by affecting expression of aryl hydrocarbon receptor (Ahr) and inflammatory cytokines in animal models. As the role of the Ahr in dioxin-exposed people is not well defined, a study was conducted to examine gene expression levels of Ahr, inflammatory cytokines, and the incidence of diseases in dioxin-exposed citizens who had/still resided near a heavily dioxin-contaminated area in Vietnam. Whole blood from citizens at/around Da Nang airbase and control individuals living in unsprayed areas was collected. Serum levels of dioxins were analyzed by using a dioxins-responsive chemical-activated luciferase gene expression bioassay. Gene expression of Ahr, interleukin (IL)-1β, TNFα, IL-6, and IL-22 in whole blood was examined by quantitative real-time PCR. The results showed levels of dioxins and expression of Ahr, IL-1β, TNFα, and IL-6 were up-regulated while IL-22 expression was down-regulated in dioxin-exposed people. Various disease incidences in the study subjects was also examined. Interestingly, the incidence of rheumatoid arthritis (RA) in these individuals was increased compared to the estimated prevalence of this disease in the general Vietnamese population. Analyses also showed that expression levels of Ahr correlated to those of IL-6 and IL-22 in the dioxin-exposed people. Taken together, dioxins might be involved in an up-regulated expression of Ahr that might possibly relate to changes in level of inflammatory cytokines and, ultimately, in the incidence of select diseases in residents of Vietnam who had/continue to live near a dioxins-contaminated site.

Korean red ginseng ameliorated experimental pancreatitis through the inhibition of hydrogen sulfide in mice.

Effective therapy to treat acute pancreatitis (AP) or to prevent its recurrence/complication is still not available. Based on previous results that suggest that: i) hydrogen sulfide (H2S) levels were significantly increased in pancreatitis and gastritis and ii) Korean red ginseng (KRG) efficiently attenuated Helicobacter pylori-associated gastritis through the suppressive actions of H2S, we hypothesized that KRG can ameliorate experimental pancreatitis through suppression of H2S generation. C57BL/6 mice were pre-administered KRG and then subjected to cerulein injection or pancreatic duct ligation (PDL) to induce pancreatitis. Blood and pancreas tissues were collected and processed to measure serum levels of amylase, lipase and myeloperoxidase and the concentration of H2S and the levels of various inflammatory cytokine in pancreatic tissues of mice with induced AP. KRG significantly inhibited NaHS-induced COX-2 and TNF-α mRNA in pancreatic cells, but dl-propargylglycine did not. KRG ameliorated cerulein-induced edematous pancreatitis accompanied with significant inactivation of NF-κB and JNK in pancreatic tissues of C57BL/6 mice (p<0.001) and also significantly ameliorated PDL-induced necrotizing pancreatitis (p<0.01); in both conditions, the significant suppression of H2S resulting from KRG pretreatment afforded rescuing outcomes. Along with suppressed levels of H2S consequent to depressed expressions of CBS and CSE mRNA, KRG administration efficiently decreased the serum level of amylase, lipase, and myeloperoxidase and the expression of inflammatory cytokines in animal models of mild or severe AP. These results provide evidence for the preventive and therapeutic roles of KRG against AP mediated by H2S suppression.

Targeting the Binding Interface on a Shared Receptor Subunit of a Cytokine Family Enables the Inhibition of Multiple Member Cytokines with Selectable Target Spectrum

The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases.

Role of the Immune System in Hypertension: Modulation by Dietary Antioxidants

Hypertension is a major health problem worldwide. Individuals with hypertension are at an increased risk for stroke, heart disease, and kidney failure. Although the etiology of essential hypertension has a genetic component, lifestyle factors such as diet play an important role. Insulin resistance is a common feature of hypertension in both humans and animal models affecting glucose and lipid metabolism producing excess aldehydes including methylglyoxal. These aldehydes react with proteins to form conjugates called advanced glycation end products (AGEs). This alters protein structure and function and can affect vascular and immune cells leading to their activation and secretion of inflammatory cytokines. AGEs also act via receptors for advanced glycation end products on these cells altering the function of antioxidant and metabolic enzymes, and ion channels. This results in an increase in cytosolic free calcium, decrease in nitric oxide, endothelial dysfunction, oxidative stress, peripheral vascular resistance, and infiltration of vascular and kidney tissue with inflammatory cells leading to hypertension. Supplementation with dietary antioxidants including vitamins C, E, or B(6), thiols such as cysteine and lipoic acid, have been shown to lower blood pressure and plasma inflammatory cytokines in animal models and humans with essential hypertension. A well-balanced diet rich in antioxidants that includes vegetables, fruits, low fat dairy products, low salt, and includes whole grains, poultry, fish and nuts, lowers blood pressure and vascular inflammation. These antioxidants may achieve their antihypertensive and anti-inflammatory/immunomodulatory effects by reducing AGEs and improving insulin resistance and associated alterations. Dietary supplementation with antioxidants may be a beneficial, inexpensive, front-line alterative treatment modality for hypertension.

Evaluation of the Effect of Bosentan Treatment on Proinflammatory Cytokine Serum Levels in Patients Affected by Systemic Sclerosis

Systemic sclerosis (SSc) is a connective tissue disease characterized by vascular and fibrotic changes in the skin and in internal organs. Endothelin-1 (ET-1) is a peptide that has a role in promoting both vascular injury and the fibrotic process in SSc; indeed, patients with systemic sclerosis have higher levels of ET-1 compared with healthy subjects. Moreover, ET-1 enhances expression of pro-inflammatory cytokines in animal model. Bosentan is a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension and digital ulcers in scleroderma patients. In animal models and in vitro models, after treatment with Bosentan, a significant reduction of cytokine (TNF α, IFN γ,IL-8, IL-4) levels was observed. The aim of the study is to verify whether Bosentan treatment in SSc patients can reduce circulating cytokines levels. We enrolled 10 patients affected by SSc with digital ulcers and/or pulmonary hypertension, treated with Bosentan 125 mg twice daily. Patients were tested for cytokines and ET-1 level before treatment and after 12 months. The cytokines tested were IL-10, IL-2, IL-4, IL-5, IL-6, IL-8, GM-CSF, IFN-γ and TNF. Levels of ET-1, IL-10, IL-4, IL-5, GM-CSF and TNFalpha did not show consistent modification during treatment with Bosentan in respect to baseline, while IL-2, IL-6, IL-8 and IFN-γ were significantly decreased. Bosentan significantly reduced IL-2, IL-6, IL-8 and IFN- γ levels in SSc patients, probably slowing progression to fibrosis and vascular damage. This is the first report showing a decrease of profibrotic and proinflammatory cytokines levels in humans during treatment with Bosentan.

Immunomodulation of the epithelial cell responses by CD80 blockade and disease amelioration in experimental colitis. (89.3)

Abstract Under physiological conditions the intestinal epithelium adapts to a constantly changing environment of the intestinal luminal content including the enteric bacteria. The colonic epithelial cells (CEC) respond to microbes through a family of tightly regulated toll like receptors (TLR) that constantly survey their surroundings for potential threats. In inflammatory bowel diseases (IBD) abnormal response to bacteria mobilizes immune effector cells to the intestinal mucosa, chiefly the CD4+ T cells which perpetuate sustained inflammation. Successful therapeutic strategies for IBD should therefore suppress lymphocytic responses; promote epithelial healing and re-establishment of intestinal homeostasis. Inhibition of T cell activation suppresses inflammatory cytokines in animal models of IBD. Here we investigated the effects of a synthetic peptide that blocks T cell costimulation, the CD80-CAP, on the CEC responses in experimental colitis. We observed that the CEC from CD80-CAP treated mice exhibited significantly reduced pro-inflammatory responses and a skewing towards anti-inflammatory cytokine response. Importantly, the CD80-CAP treatment also resulted in concomitant restoration of TLR-2, TLR-3, TLR-4 and TLR-5 mRNA in the CEC of colitic mice to physiologic levels. Taken together our data suggest that the CD80-CAP administration suppress inflammation and modulate epithelial cell responses potentially facilitating re-establishment of mucosal homeostasis in experimental colitis.

Estrogen decreases inflammation and apoptotic signaling in the heart following severe burn injury

Patients with severe burn injury experience a rapid elevation in multiple circulating proinflammatory cytokines, with the levels correlating with both injury severity and outcome. Accumulations of these cytokines in animal models have been observed in remote organs, however data are lacking regarding early serial heart cytokine levels following burn injury, and the therapeutic effects of estrogen on these levels. Using an animal model, we studied the acute effects of a full-thickness third-degree burn on cardiac levels of IL-1β, IL-6, IL-10, and TNFα. In addition, we analyzed the effect of estrogen on levels of cytochrome C, signifying apoptosis, and levels of NF-κB, signifying inflammation. Here, we hypothesized that acute estrogen treatment decreases inflammation in the heart and blocks the induction of apoptosis.

Estrogen treatment following severe burn injury reduces brain inflammation and apoptotic signaling

BackgroundPatients with severe burn injury experience a rapid elevation in multiple circulating pro-inflammatory cytokines, with the levels correlating with both injury severity and outcome. Accumulations of these cytokines in animal models have been observed in remote organs, however data are lacking regarding early brain cytokine levels following burn injury, and the effects of estradiol on these levels. Using an experimental animal model, we studied the acute effects of a full-thickness third degree burn on brain levels of TNF-α, IL-1β, and IL-6 and the protective effects of acute estrogen treatment on these levels. Additionally, the acute administration of estrogen on regulation of inflammatory and apoptotic events in the brain following severe burn injury were studied through measuring the levels of phospho-ERK, phospho-Akt, active caspase-3, and PARP cleavage in the placebo and estrogen treated groups.MethodsIn this study, 149 adult Sprague-Dawley male rats received 3rd degree 40% total body surface area (TBSA) burns. Fifteen minutes following burn injury, the animals received a subcutaneous injection of either placebo (n = 72) or 17 beta-estradiol (n = 72). Brains were harvested at 0.5, 1, 2, 4, 6, 8, 12, 18, and 24 hours after injury from the control (n = 5), placebo (n = 8/time point), and estrogen treated animals (n = 8/time point). The brain cytokine levels were measured using the ELISA method. In addition, we assessed the levels of phosphorylated-ERK, phosphorylated-Akt, active caspase-3, and the levels of cleaved PARP at the 24 hour time-point using Western blot analysis.ResultsIn burned rats, 17 beta-estradiol significantly decreased the levels of brain tissue TNF-α (~25%), IL-1β (~60%), and IL-6 (~90%) when compared to the placebo group. In addition, we determined that in the estrogen-treated rats there was an increase in the levels of phospho-ERK (p < 0.01) and Akt (p < 0.05) at the 24 hour time-point, and that 17 beta-estradiol blocked the activation of caspase-3 (p < 0.01) and subsequent cleavage of PARP (p < 0.05).ConclusionFollowing severe burn injury, estrogens decrease both brain inflammation and the activation of apoptosis, represented by an increase in the levels of phospho-Akt and inhibition of caspase-3 activation and PARP cleavage. Results from these studies will help further our understanding of how estrogens protect the brain following burn injury, and may provide a novel, safe, and effective clinical treatment to combat remote secondary burn injury in the brain and to preserve cognition.

Gene therapy for posterior uveitis

Abstract Purpose To investigate the role of gene therapy incorporating release of immunomodulatory cytokines in animal models of intraocular inflammation Methods By inoculating with either AAV or lente viruses incorporating genes for IL‐1RA or IL‐10 into either the anterior chamber or subretinally we onserved the ability to suppress either endotoxin induced uveitis (EIU) or experimental autoimmiune uveoretinitis (EAU). Results Anterior chamber inoculation with lente‐IL‐10 or IL‐1RA successfully suppresses inflammation and protein exudation into the eye during the course of EIU. Subretinal injection of AAV‐IL‐10 suppresses EAU. The extent of local macrophage activation is also suppressed as there is marked reduction in nitrotyrosine expression within the retina. Conclusion Gene therapy with immunomodulatory cytokines offers a potential to suppress active inflammatory processes within the retina. Mechanisms will be discussed in the talk in relation to macrophage activation and restoring myeloid cell (microgolial) homeostasis within the retina.