Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se— not by lipoprotein contaminants

2005 ◽  
Vol 289 (2) ◽  
pp. R348-R352 ◽  
Author(s):  
Alexandre A. Steiner ◽  
Sumana Chakravarty ◽  
Jared R. Robbins ◽  
Alexander S. Dragic ◽  
Jennifer Pan ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Serum Levels ◽  
Toll Like Receptor ◽  
Tlr4 Signaling ◽  
Highly Active ◽  
Cytokine Responses ◽  
Tnf Α ◽  
Per Se ◽  
Phenol Water

LPS preparations cause a variety of body temperature (Tb) responses: monophasic fever, different phases of polyphasic fever, and hypothermia. Conventional (c) LPS preparations contain highly active lipoprotein contaminants (endotoxin proteins). Whereas LPS signals predominantly via the Toll-like receptor (TLR) 4, endotoxin proteins signal via TLR2. Several TLR2-dependent responses of immunocytes to cLPS in vitro are triggered by endotoxin proteins and not by LPS itself. We tested whether any Tb response to cLPS from Escherichia coli 055:B5 is triggered by non-TLR4-signaling contaminants. A decontaminated (d) LPS preparation (free of endotoxin proteins) was produced by subjecting cLPS to phenol-water reextraction. The presence of non-TLR4-signaling contaminants in cLPS (and their absence in dLPS) was confirmed by showing that cLPS (but not dLPS) induced IL-1β expression in the spleen and increased serum levels of TNF-α and IL-1β of C3H/HeJ mice; these mice bear a nonfunctional TLR4. Yet, both cLPS and dLPS caused cytokine responses in C3H/HeOuJ mice; these mice bear a fully functional TLR4. We then studied the Tb responses to cLPS and dLPS in Wistar rats preimplanted with jugular catheters. At a neutral ambient temperature (30°C), a low (0.1 μg/kg iv) dose of cLPS caused a monophasic fever, whereas a moderate (10 μg/kg iv) dose produced a polyphasic fever. In the cold (20°C), a high (500 μg/kg iv) dose of cLPS caused hypothermia. All Tb responses to dLPS were identical to those of cLPS. We conclude that all known Tb responses to LPS preparations are triggered by LPS per se and not by non-TLR4-signaling contaminants of such preparations.

scholarly journals Toll-like receptor 2 dominance over Toll-like receptor 4 in stressful conditions for its detrimental role in the heart

2017 ◽  
Vol 312 (6) ◽  
pp. H1238-H1247 ◽  
Author(s):  
Ashim K. Bagchi ◽  
Gauri Akolkar ◽  
Soma Mandal ◽  
Prathapan Ayyappan ◽  
Xi Yang ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Myeloid Differentiation ◽  
Type I ◽  
Toll Like Receptor ◽  
Tlr4 Signaling ◽  
Tnf Α ◽  
Differentiation Gene

It has been suggested that Toll-like receptor (TLR)4 promotes IL-10-mediated cardiac cell survival, whereas another receptor, TLR2, from the same family, is detrimental. Here, we examined the interactive role of these two innate signaling molecules under stressful conditions, including IL-10 knockout (IL-10−/−) mice, global ischemia-reperfusion (I/R) injury in rat hearts, and in vitro short hairpin RNA experimental models in the presence or absence of IL-10 (10 ng/ml). Circulating and myocardial levels of TNF-α as well as apoptosis and fibrosis were higher in IL-10−/− mice. The increase in TLR2 in IL-10−/− hearts indicated its negative regulation by IL-10. Ex vivo I/R also caused a marked upregulation of TLR2 and TNF-α as well as apoptotic and fibrotic signals. However, a 40-min reperfusion with IL-10 triggered an increase in TLR4 expression and improved recovery of cardiac function. The increase in IL-1 receptor-associated kinase (IRAK)-M and IRAK-2 activity during I/R injury suggested their role in TLR2 signaling. In vitro inhibition of TLR4 activity as a consequence of RNA inhibition-mediated suppression of myeloid differentiation gene (MyD)88 suggested MyD88-dependent activation of TLR4. The inclusion of IL-10 during reperfusion also downregulated the expression of IRAK-2, TNF-α receptor-associated factor 1-interacting protein (TRAIP) and apoptotic signals, caspase-3, and the Bax-to-Bcl-xL ratio. IL-10 reduced the TNF-α receptor-associated increase in TRAIP-induced apoptosis during I/R injury, which led to an increase in IL-1β to mitigate transforming growth factor-β receptor type I-mediated fibrosis. The IL-10 mitigation of these changes suggests that the stimulation through TLR4 signaling promotes IRAK-4 and phosphorylates IRAK-1 instead of IRAK-2 and may be an important therapeutic approach in restoring heart health in stress. NEW & NOTEWORTHY Under stress conditions such as downregulation of the IL-10 gene or ischemia-reperfusion injury, Toll-like receptor (TLR)4 and IL-1 receptor-associated kinase (IRAK)-1 activation is suppressed, along with the upregulation of TLR-2 and IRAK-2, resulting in fibrosis and apoptosis. It is suggested that IL-10 helps to maintain heart function during stress via myeloid differentiation gene 88/IRAK-4/IRAK-1-dependent TLR4 signaling.

scholarly journals Dipterocarpus tuberculatus Roxb. Ethanol Extract Has Anti-Inflammatory and Hepatoprotective Effects In Vitro and In Vivo by Targeting the IRAK1/AP-1 Pathway

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2529
Author(s):  
Haeyeop Kim ◽  
Woo Seok Yang ◽  
Khin Myo Htwe ◽  
Mi-Nam Lee ◽  
Young-Dong Kim ◽  
...  
Keyword(s):  
Ethanol Extract ◽  
Serum Levels ◽  
Hepatoprotective Activity ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Related Proteins ◽  
Pro Inflammatory Cytokines ◽  
Inflammatory Effect

Dipterocarpus tuberculatus Roxb. has been used traditionally as a remedy for many diseases, especially inflammation. Therefore, we analyzed and explored the mechanism of the anti-inflammatory effect of a Dipterocarpus tuberculatus Roxb. ethanol extract (Dt-EE). Dt-EE clearly and dose-dependently inhibited the expression of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells. Also, Dt-EE suppressed the activation of the MyD88/TRIF-mediated AP-1 pathway and the AP-1 pathway related proteins JNK2, MKK4/7, and TAK1, which occurred as a result of inhibiting the kinase activity of IRAK1 and IRAK4, the most upstream factors of the AP-1 pathway. Finally, Dt-EE displayed hepatoprotective activity in a mouse model of hepatitis induced with LPS/D-galactosamine (D-GalN) through decreasing the serum levels of alanine aminotransferase and suppressing the activation of JNK and IRAK1. Therefore, our results strongly suggest that Dt-EE could be a candidate anti-inflammatory herbal medicine with IRAK1/AP-1 inhibitory and hepatoprotective properties.

scholarly journals In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 615
Author(s):  
Shang-En Huang ◽  
Erna Sulistyowati ◽  
Yu-Ying Chao ◽  
Bin-Nan Wu ◽  
Zen-Kong Dai ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Serum Levels ◽  
Gene Expressions ◽  
Tnf Α ◽  
Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

scholarly journals Cytokine dysregulation persists in childhood post Neonatal Encephalopathy

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zunera Zareen ◽  
Tammy Strickland ◽  
Victoria Mc Eneaney ◽  
Lynne A. Kelly ◽  
Denise McDonald ◽  
...  
Keyword(s):  
School Age Children ◽  
Therapeutic Window ◽  
School Age ◽  
Neonatal Encephalopathy ◽  
Gm Csf ◽  
Cytokine Responses ◽  
Tnf Α ◽  
Cytokine Dysregulation ◽  
Macrophage Colony

Abstract Background Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls. Method Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF β, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin). Results GM-CSF, TNF-β, IL-2 IL-6 and IL-8 were significantly elevated at school age following NE (n = 40) compared to controls (n = 37). A rise in GM-CSF, IL-8, TNF-α, IL-1β, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-β. Elevated TNF-β was associated with low gross motor scores on assessment at school age. Conclusion School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-β was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for neuroprotection therapies.

scholarly journals Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14- and Toll-Like Receptor 4-Dependent Manner

2001 ◽  
Vol 69 (4) ◽  
pp. 2025-2030 ◽  
Author(s):  
Shuhua Yang ◽  
Shunji Sugawara ◽  
Toshihiko Monodane ◽  
Masahiro Nishijima ◽  
Yoshiyuki Adachi ◽  
...  
Keyword(s):  
Lipid A ◽  
Micrococcus Luteus ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Monocytic Cells ◽  
Tnf Α

ABSTRACT Teichuronic acid (TUA), a component of the cell walls of the gram-positive organism Micrococcus luteus (formerlyMicrococcus lysodeikticus), induced inflammatory cytokines in C3H/HeN mice but not in lipopolysaccharide (LPS)-resistant C3H/HeJ mice that have a defect in the Toll-like receptor 4 (TLR4) gene, both in vivo and in vitro, similarly to LPS (T. Monodane, Y. Kawabata, S. Yang, S. Hase, and H. Takada, J. Med. Microbiol. 50:4–12, 2001). In this study, we found that purified TUA (p-TUA) induced tumor necrosis factor alpha (TNF-α) in murine monocytic J774.1 cells but not in mutant LR-9 cells expressing membrane CD14 at a lower level than the parent J774.1 cells. The TNF-α-inducing activity of p-TUA in J774.1 cells was completely inhibited by anti-mouse CD14 monoclonal antibody (MAb). p-TUA also induced interleukin-8 (IL-8) in human monocytic THP-1 cells differentiated to macrophage-like cells expressing CD14. Anti-human CD14 MAb, anti-human TLR4 MAb, and synthetic lipid A precursor IVA, an LPS antagonist, almost completely inhibited the IL-8-inducing ability of p-TUA, as well as LPS, in the differentiated THP-1 cells. Reduced p-TUA did not exhibit any activities in J774.1 or THP-1 cells. These findings strongly suggested that M. luteus TUA activates murine and human monocytic cells in a CD14- and TLR4-dependent manner, similar to LPS.

scholarly journals Cytokine Dysregulation Persists in Childhood Post Neonatal Encephalopathy

2019 ◽  
Author(s):  
Zunera Zareen ◽  
Tammy Strickland ◽  
Victoria Mc Eneaney ◽  
Lynne A. Kelly ◽  
Denise McDonald ◽  
...  
Keyword(s):  
Significant Rise ◽  
School Age Children ◽  
Therapeutic Window ◽  
School Age ◽  
Neonatal Encephalopathy ◽  
Gm Csf ◽  
Cytokine Responses ◽  
Tnf Α ◽  
Cytokine Dysregulation

Abstract Objective: Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls. Method: Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF β, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin). Results: GM­-CSF, TNF-β, IL-2 IL-6, IL-8, IL-10, and IL-18 were significantly elevated at school age following NE (n=40) compared to controls (n=37). A significant rise in GM-CSF, IL-8, TNF-α, IL-1β, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-β. Elevated TNF-β was associated with low gross motor scores on assessment at school age. Conclusion: School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-β was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for immunomodulatory adjunctive therapies.

scholarly journals Emodin ameliorates renal injury in BXSB mice by modulating TNF-α/ICAM-1

2020 ◽  
Vol 40 (9) ◽  
Author(s):  
Xinlu Yuan ◽  
Binbin Dai ◽  
Liyan Yang ◽  
Beiduo Lin ◽  
Enqin Lin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Renal Injury ◽  
Serum Levels ◽  
Intercellular Adhesion Molecule ◽  
Dependent Manner ◽  
Urine Protein ◽  
Tnf Α ◽  
Dsdna Antibody ◽  
Bxsb Mice

Abstract The purpose of the present study was to explore the effects of emodin on renal injury in a BXSB mouse model of lupus and its mechanisms. BXSB mice were fed different concentrations of emodin (0, 5, 10 and 20 mg/kg.d), and the levels of intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) and fibronectin (FN) levels in the glomeruli and serum levels of the anti-dsDNA antibody were determined. Mesangial cells (MCs) were cultured in vitro, and IgG-type anti-dsDNA antibody and/or emodin were added to the MC culture supernatant. In addition, TNF-α small interfering RNA (siRNA) was transfected into MCs to explore the mechanism of action of emodin. The results showed that the mice fed emodin presented decreases in the urinary protein content and glomerular TNF-α, ICAM-1 and FN levels (P<0.05). Moreover, the urine protein, TNF-α, ICAM-1 and FN levels were decreased in a dose-dependent manner (P<0.05). In vitro, the anti-dsDNA antibody group exhibited increased levels of ICAM-1 and TNF-α (P<0.05), and the anti-dsDNA antibody group showed myofibroblast-like structural changes. The aforementioned indexes were decreased in the emodin group (P<0.05), and the extent of transdifferentiation was significantly reduced. Moreover, the level of ICAM-1 decreased with the down-regulation of TNF-α (P<0.05). Emodin reduced the urine protein levels and serum levels of the anti-dsDNA antibody in a mouse model of lupus nephritis (LN). The underlying mechanism may be related to decreased levels of TNF-α, ICAM-1 and FN and the inhibition of dsDNA antibody-induced MC damage.

scholarly journals L-Carnitine Ameliorates the Muscle Wasting of Cancer Cachexia through the AKT/FOXO3a/MaFbx Axis

2021 ◽  
Author(s):  
Changpeng Wu ◽  
Mingxing Zhu ◽  
Zongliang Lu ◽  
Yaowen Zhang ◽  
Long Li ◽  
...  
Keyword(s):  
Cancer Cachexia ◽  
Muscle Protein ◽  
Interleukin 1 ◽  
Serum Levels ◽  
C2c12 Cells ◽  
Cross Sectional ◽  
Protein Ubiquitination ◽  
Tnf Α

Abstract Recent studies suggest potential benefits of applying L-carnitine in the treatment of cancer cachexia, but the precise mechanisms remain unknown. This study was conducted to determine the mechanism by which L-carnitine reduces cancer cachexia. We found that L-carnitine increased the gastrocnemius muscle (GM) weight in the CT-26-bearing cachexia mouse model and the cross-sectional fiber area (CFA) of the GM and myotube diameters of C2C12 cells treated with TNF-α. Additionally, L-carnitine reduced the protein expression of muscle RING-type E3 ubiquitin ligase 1 (MuRF1), muscle atrophy F-box protein (MaFbx) and FOXO3a, and increased the p-FOXO3a level in vivo and in vitro, indicating that L-carnitine inhibits muscle protein ubiquitination in models of cachexia. Inhibition of Akt, upstream of FOXO3a, reversed the effects of L-carnitine on the FOXO3a/MaFbx pathway and myotube diameters, without affecting FOXO3a/MuRF-1. In addition to regulating the ubiquitination of muscle proteins, L-carnitine also increased the levels of p-p70S6K and p70S6K, which are involved in protein synthesis. Akt inhibition did not reverse the effects of L-carnitine on p70S6K. Hence, L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx and p70S6K pathways. Moreover, L-carnitine reduced the serum levels of interleukin-1 (IL-1) and interleukin-6 (IL-6), factors known to induce cancer cachexia. However, there were minimal effects on TNF-α, another inducer of cachexia. Taken together, these results revealed a novel mechanism of action by which L-carnitine protects muscle cells and reduces inflammation related to cancer cachexia.

scholarly journals Altered Cytokine Production and Impaired Antimycobacterial Immunity in Protein-Malnourished Guinea Pigs

1998 ◽  
Vol 66 (8) ◽  
pp. 3562-3568 ◽  
Author(s):  
Guixiang Dai ◽  
David N. McMurray
Keyword(s):  
Transforming Growth Factor Beta ◽  
Guinea Pigs ◽  
Transforming Growth Factor ◽  
Serum Levels ◽  
Peritoneal Macrophages ◽  
Protein Malnutrition ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Cd4 Lymphocytes

ABSTRACT Protein malnutrition leads to multiple detrimental alterations of host immune responses to mycobacterial infection. In this study, we demonstrated that splenocytes from low-protein (LP) guinea pigs vaccinated 6 weeks previously with attenuated Mycobacterium tuberculosis H37Ra failed to control the accumulation of virulentM. tuberculosis H37Rv in cocultured autologous peritoneal macrophages, despite the fact that they were able to control the accumulation of virulent tubercle bacilli in cocultured syngeneic peritoneal macrophages from normally nourished guinea pigs as successfully as did those from high-protein (HP) counterparts. Vaccine-induced growth control of virulent M. tuberculosisH37Rv in these cocultures appeared to be mediated by CD4 lymphocytes but not CD8 cells. Tuberculin (purified protein derivative [PPD])-induced lymphoproliferation was markedly impaired in vaccinated LP guinea pigs, and the depletion of CD4 lymphocytes significantly decreased lymphocyte proliferation whereas CD8 cell depletion did not. Protein malnutrition also impaired the abilities of cells from vaccinated LP guinea pigs to produce cytokines, including interferon, tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β), in response to PPD, despite the demonstration of higher serum levels of TNF-α and TGF-β after an intravenous injection of PPD into LP guinea pigs. In contrast, peritoneal macrophages from protein-malnourished guinea pigs produced a higher level of TGF-β 4 days after infection in vitro with M. tuberculosis H37Rv than did those from protein adequate controls. These results suggest that dietary protein malnutrition impairs vaccine-induced resistance to M. tuberculosis, in part, by altering the cytokine profile to favor macrophage deactivation.

scholarly journals Cytokine Dysregulation Persists in Childhood Post Neonatal Encephalopathy

2020 ◽  
Author(s):  
Zunera Zareen ◽  
Tammy Strickland ◽  
Victoria Mc Eneaney ◽  
Lynne A. Kelly ◽  
Denise McDonald ◽  
...  
Keyword(s):  
Significant Rise ◽  
School Age Children ◽  
Therapeutic Window ◽  
School Age ◽  
Neonatal Encephalopathy ◽  
Gm Csf ◽  
Cytokine Responses ◽  
Tnf Α ◽  
Cytokine Dysregulation

Abstract Background: Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE) . Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls. Method: Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF β, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin). Results: GM­-CSF, TNF-β, IL-2 IL-6, IL-8, IL-10, and IL-18 were significantly elevated at school age following NE (n=40) compared to controls (n=37). A significant rise in GM-CSF, IL-8, TNF-α, IL-1β, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-β. Elevated TNF-β was associated with low gross motor scores on assessment at school age. Conclusion: School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-β was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for neuroprotection therapies.

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