Acute Suppression of Circulating sCD40L During Hyperglycemia and Euglycemic-Hyperinsulinemia in Healthy Young Males

sCD40L is a proatherogenic cytokine, part of the tumor necrosis factor (TNF) superfamily and consistently associated with obesity, diabetes, and increased cardiovascular risk. Although the role of sCD40L in the onset/progression of cardiovascular complications of dysmetabolic diseases may be modulated by acute and/or chronic fluctuations of plasma insulin and glucose, very little has been done to clarify this interaction. The kinetic profile of sCD40L (and, in an exploratory manner, of several immunomodulatory factors), were measured during hyperglycemia and euglycemic-hyperinsulinemia in a group of 10 healthy young males (26.8 ± 1.4 years). After an overnight fast, intravenous (iv) catheters were placed in antecubital veins of both arms for blood drawing and dextrose/insulin iv infusions. Procedures lasted 240 minutes including baseline (t = 0-60), hyperglycemia (t = 60-150; plasma glucose ∼220 mg/dL via iv dextrose infusion), and euglycemic-hyperinsulinemia (t = 150-240; glucose infusion continued to clamp glycemic levels between 80 and 110 mg/dL; constant insulin infusion at 1.5 mU/kg/minute).Plasma for cytokine assays was sampled at 12 separate time-points. Plasma levels of sCD40L were significantly reduced (P < 0.01) during hyperglycemia and euglycemic-hyperinsulinemia, paralleling the kinetic profiles of free fatty acids and ketone bodies. This pattern was also observed in other immunomodulatory factors (notably cortisol and epidermal growth factor), while (interleukin [IL]-1α, IL-4, IL-6, IL-9, IL-10, TNF-α, Eotaxin) did not change significantly. Significant reductions of the proatherogenic cytokine sCD40L were observed during endogenous and exogenous hyperinsulinemia, independent of prevailing glucose concentration, in young healthy males. Our data suggest a mechanism by which correct insulin action may exert a beneficial protective role against inflammation, independent of its immediate glucose-lowering effect.

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Macrophage migration inhibitory factor may play a protective role in osteoarthritis

Arthritis Research & Therapy ◽

10.1186/s13075-021-02442-w ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Ming Liu ◽

Zikun Xie ◽

Guang Sun ◽

Liujun Chen ◽

Dake Qi ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Protective Role ◽

Macrophage Migration ◽

Chain Reaction ◽

Protein Levels ◽

Tnf Α ◽

Polymerase Chain

Abstract Background Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. Methods One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured by enzyme-linked immunosorbent assay. Results rs755622 and -794 CATT5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10−10), while the levels of TNF-α, IL-6 and IL-1β in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1β protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04–0.19 and 4.42–16.82, respectively), but TNF-α and IL-6 became non-significant. Conclusions Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

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Abstract 507: Activation of the Classically Pro-Apoptotic Death Receptor 5 Promotes Physiological Hypertrophy and Cardiomyocyte Survival

Circulation Research ◽

10.1161/res.127.suppl_1.507 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Toby Thomas ◽

Miles Tanner ◽

Laurel Grisanti

Keyword(s):

Heart Failure ◽

Cell Death ◽

Cardiac Fibrosis ◽

Death Receptor ◽

Protective Role ◽

Cardiomyocyte Hypertrophy ◽

Death Receptor 5 ◽

Tnf Α ◽

Cardiomyocyte Survival

Heart failure is hallmarked by a combination of cardiomyocyte hypertrophy and death. Apoptosis, one of the primary mechanisms of cell death, occurs through finely tuned extrinsic or intrinsic pathways. Of the mediators involved in extrinsic apoptotic signaling, some have been extensively studied, such as tumor necrosis factor ((TNF)-α), while others have been relatively untouched. One such receptor is Death Receptor 5 (DR5) which, along with its ligand TNF-Related Apoptosis Inducing Ligand (TRAIL), have recently been implicated as a biomarker in determining the progression and outcome in patients following multiple heart failure etiologies, suggesting a novel role of DR5 signaling in the heart. These studies suggest a potentially protective role for DR5 in the heart; however, the function of TRAIL/DR5 in the heart has been virtually unstudied. Our goal was to explore the role of TRAIL/DR5 in cardiomyocyte hypertrophy and survival with the hypothesis that DR5 promotes cardiomyocyte survival and growth through non-canonical mechanisms. Mice treated with the DR5 agonist bioymifi or a DR5 agonist antibody, MD5-1, were absent of cell death, while an increase in hypertrophy was observed without a decline in cardiac function. In isolated cardiomyocytes, this pro-hypertrophic phenotype was determined to operate through MMP-dependent cleavage of HB-EGFR, leading to transactivation of EGFR and ERK1/2 signaling. To determine the role of DR5 in heart failure, a chronic catecholamine administration model was used and DR5 activation was found to decrease cardiomyocyte death and cardiac fibrosis. ERK1/2, a well characterized pro-survival, pro-hypertrophic kinase is activated in the heart with DR5 agonist administration and may represent the mechanistic link through which DR5 is imparting cardioprotection. In summary, DR5 activation promotes cardiomyocyte hypertrophy and survival and prevents cardiac fibrosis via a non-canonical MMP-EGFR-ERK1/2 pathway. Taken together, these studies identify a previously undetermined role for DR5 in the heart and identify novel therapeutic target for the treatment of heart failure.

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Gastroprotective and vasodilatory effects of epidermal growth factor: the role of sensory afferent neurons

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.280.5.g897 ◽

2001 ◽

Vol 280 (5) ◽

pp. G897-G903 ◽

Cited By ~ 9

Author(s):

Yoji Matsumoto ◽

Kohki Kanamoto ◽

Keishi Kawakubo ◽

Hitoshi Aomi ◽

Takayuki Matsumoto ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Mucosal Injury ◽

Protective Role ◽

Sensory Nerves ◽

Afferent Neurons ◽

Gastric Mucosal Lesions ◽

Calcitonin Gene ◽

Epidermal Growth

Epidermal growth factor (EGF) has been shown to exert gastric hyperemic and gastroprotective effects via capsaicin-sensitive afferent neurons, including the release of calcitonin gene-related peptide (CGRP). We examined the protective and vasodilatory effects of EGF on the gastric mucosa and its interaction with sensory nerves, CGRP, and nitric oxide (NO) in anesthetized rats. Intragastric EGF (10 or 30 μg) significantly reduced gastric mucosal lesions induced by intragastric 60% ethanol (50.6% by 10 μg EGF and 70.0% by 30 μg EGF). The protective effect of EGF was significantly inhibited by pretreatment with capsaicin desensitization, human CGRP1 antagonist hCGRP-(8–37), or N ω-nitro-l-arginine methyl ester (l-NAME). Intravital microscopy showed that topically applied EGF (10–1,000 μg/ml) dilated the gastric mucosal arterioles dose dependently and that this vasodilatory effect was significantly inhibited by equivalent pretreatments. These findings suggest that EGF plays a protective role against ethanol-induced gastric mucosal injury, possibly by dilating the gastric mucosal arterioles via capsaicin-sensitive afferent neurons involving CGRP and NO mechanisms.

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Protective role of betulinic acid on TNF-α-induced cell adhesion molecules in vascular endothelial cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2009.11.009 ◽

2010 ◽

Vol 391 (1) ◽

pp. 96-101 ◽

Cited By ~ 41

Author(s):

Jung Joo Yoon ◽

Yun Jung Lee ◽

Jin Sook Kim ◽

Dae Gill Kang ◽

Ho Sub Lee

Keyword(s):

Endothelial Cells ◽

Cell Adhesion ◽

Adhesion Molecules ◽

Betulinic Acid ◽

Cell Adhesion Molecules ◽

Vascular Endothelial Cells ◽

Protective Role ◽

Vascular Endothelial ◽

Tnf Α

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Ischemia in normoglycemic and hyperglycemic rats: plasma energy substrates and hormones

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.5.e767 ◽

1990 ◽

Vol 258 (5) ◽

pp. E767-E774

Author(s):

J. Lundgren ◽

A. Mans ◽

B. K. Siesjo

Keyword(s):

Ketone Bodies ◽

Plasma Concentrations ◽

Plasma Corticosterone ◽

Rat Plasma ◽

Protective Role ◽

Forebrain Ischemia ◽

Energy Substrates ◽

Plasma Energy ◽

Membrane Changes

Seizures are a documented complication to cerebral ischemia. After 10 min of forebrain ischemia in rats, preischemic hyperglycemia invariably leads to severe, most often fatal epileptic attacks. This outcome is related to the exaggerated lactic acidosis, which has been suggested as a possible contributor to severe membrane changes and widespread edema. To find out if circulating hormones or plasma energy substrates modulate this additive damage caused by the hyperglycemia, plasma concentrations of of corticosterone, epinephrine, norepinephrine, dopamine, glucagon, insulin, glucose, free fatty acids (FFA), 3-hydroxybutyrate, and acetoacetate were measured before and in the early recirculation period after 15 min of forebrain ischemia in the rat. Plasma corticosterone levels did not differ between the normo- and hyperglycemic groups. Although not significantly different from control, the catecholamine levels showed a tendency to be higher in the hyperglycemic groups. Therefore, because catecholamines have been reported to have a protective effect during ischemia the present result cannot explain why hyperglycemia aggravates the ischemic damage. Insulin levels seemed to increase during ischemia but not significantly. Levels quickly returned to normal after 30 min of recirculation. FFA concentrations were reduced after the induction of ischemia and appeared lower in all hyperglycemic groups. The level of one of the ketone bodies, 3-hydroxybutyrate, showed a significant decrease in hyperglycemic ischemia in all groups compared with normoglycemic ischemia. The same tendency was seen for acetoacetate. Results are compatible with a protective role of ketone bodies in ischemia. It is concluded that among the hormones and substrates studied only the ketone body concentrations qualify as a modulator of the exaggerated brain damage after ischemia in hyperglycemic subjects.

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Protective role of cytosolic 2-cys peroxiredoxin in the TNF-α-induced apoptotic death of human cancer cells

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2009.07.027 ◽

2009 ◽

Vol 47 (8) ◽

pp. 1162-1171 ◽

Cited By ~ 14

Author(s):

Joo Young Lee ◽

Hyung Jung Jung ◽

In Sung Song ◽

Mark S. Williams ◽

Chulhee Choi ◽

...

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Protective Role ◽

Human Cancer Cells ◽

Apoptotic Death ◽

Tnf Α

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AB0109 THE ROLE OF CD70 IN THE DEVELOPMENT OF RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2448 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1353.1-1355

Author(s):

S. J. Yoo ◽

S. W. Kang ◽

J. Kim ◽

I. S. Yoo ◽

C. K. Park ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cell Migration ◽

Hypoxia Inducible Factor ◽

Inflammatory Cells ◽

Migration Assay ◽

Allergy Immunol ◽

Tnf Superfamily ◽

Tnf Α ◽

Inflammatory Molecules

Background:Rheumatoid arthritis (RA) is a progressive, chronic inflammatory autoimmune disease. Pro-inflammatory molecules, activated lymphocytes, and the migration of inflammatory cells are important in the development of RA. There are many unknown causes of RA. And there are many patients who are refractory to treatment with known disease-modifying anti-rheumatic drugs. So, unknown cause of RA needs to be elucidated.CD70 is a member of the tumor necrosis factor (TNF) superfamily and a ligand for CD27. The interaction of CD70 with its receptor CD27 promotes expansion and differentiation of memory and effector T cells as well as B-cell expansion and plasma cell differentiation. Hypoxia is an important micro-environmental factor in RA synovium. Hypoxia induces activation of hypoxia inducible factor (HIF). The expression of HIF-2α is up-regulated in human RA synovium. Reactive oxygen species (ROS) has been implicated in the pathophysiology of RA.Objectives:In this study, we tried to examine the presence of CD70 in RA synovium and investigate the role of CD70 in the development of RA associated with HIF-2α and ROS.Methods:Fibroblast-like synoviocyte (FLS), peripheral blood (PB) and synovial fluid (SF) were used for experiments. FLS was stimulated with recombinant human (rh)-IL-17 and rh-TNF-α. N-acetyl-L-cysteine (NAC) was used as a ROS scavenger. HIF-2α inhibitor (PT-2385) was used for examine the effect of HIF-2α in RA-FLS. RT-PCR, qPCR, western blotting, flow-cytometry, ELISA, cell migration assay, and scratch wound assay were performed.Results:CD70 mRNA is present and elevated by stimulation with IL-17 and TNF-α in both RA-FLS and osteoarthritis (OA)-FLS (Fig 1). CD70 also expresses on the surface of RA-FLS and OA FLS (Fig 2). CD70 expression on the surface of FLS is elevated by stimulation with IL-17 and TNF-α in both RA and OA. Soluble CD27 is present higher in the supernatant of RA-SF than OA-SF (Fig 3). HIF-2α mRNA, HIF-2α protein, and the amount of ROS were all elevated after treatment with IL-17 and TNF-α in RA-FLS (Fig 4, Fig 5). CD70 expression and the amount of ROS were lowered by treatment with HIF-2α inhibitor in RA-FLS (Fig 6). Decreased amount of ROS results in decreased CD70 expression on the RA-FLS (Fig 7). CD70 influenced on cell migration directly or by HIF-2α (Fig 8).Conclusion:In this study, we found the function of CD70 in RA-FLS associated with HIF-2α and ROS. First, CD70 on RA-FLS interacts with CD27 in the RA-SF and this interaction produces sCD27 (Fig. 9) and CD70 has an influence on the migration of RA-FLS. Second, IL-17 and TNF-α are critical factors to trigger the expression of CD70, HIF-2α and ROS in RA synovium. Third, CD70 is regulated by HIF-2α associated with ROS. From these results, we suggest that CD70 may be a new therapeutic target of RA. And sCD27 also may be an important diagnostic maker of RA.References:[1]Lundy SK, Sarkar S, Tesmer LA, Fox DA. Cells of the synovium in rheumatoid arthritis. T lymphocytes. Arthritis Res Ther. 2007;9(1):202.[2]Nevius E, Gomes AC, Pereira JP. Inflammatory Cell Migration in Rheumatoid Arthritis: A Comprehensive Review. Clin Rev Allergy Immunol. 2016;51(1):59-78.[3]Bowman MR, Crimmins MA, Yetz-Aldape J, Kriz R, Kelleher K, Herrmann S. The cloning of CD70 and its identification as the ligand for CD27. J Immunol. 1994;152(4):1756-61.[4]Kitajima S, Lee KL, Fujioka M, Sun W, You J, Chia GS, et al. Hypoxia-inducible factor-2 alpha up-regulates CD70 under hypoxia and enhances anchorage-independent growth and aggressiveness in cancer cells. Oncotarget. 2018;9(27):19123-35.[5]Gaber T, Dziurla R, Tripmacher R, Burmester GR, Buttgereit F. Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do! Ann Rheum Dis. 2005;64(7):971-80.Disclosure of Interests:None declared

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Protective Role of Nitric Oxide inStaphylococcus aureus Infection in Mice

Infection and Immunity ◽

10.1128/iai.66.3.1017-1022.1998 ◽

1998 ◽

Vol 66 (3) ◽

pp. 1017-1022 ◽

Cited By ~ 65

Author(s):

Sanae Sasaki ◽

Tomisato Miura ◽

Shinsuke Nishikawa ◽

Kyogo Yamada ◽

Mayuko Hirasue ◽

...

Keyword(s):

Nitric Oxide ◽

Spleen Cell ◽

Cell Cultures ◽

Protective Role ◽

Inos Mrna ◽

No Production ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Ifn Γ

ABSTRACT This study was carried out to determine the role of nitric oxide (NO) in Staphylococcus aureus infection in mice. NO production in spleen cell cultures was induced by heat-killed S. aureus. Expression of mRNA of the inducible isoform of NO synthase (iNOS) was induced in the spleens and kidneys of S. aureus-infected mice. When mice were treated with monoclonal antibodies (MAbs) against tumor necrosis factor alpha (TNF-α) or gamma interferon (IFN-γ) before S. aureus infection, the induction of iNOS mRNA expression in the kidneys was inhibited. These MAbs also inhibited NO production in spleen cell cultures stimulated with heat-killed S. aureus. NO production in the spleen cell cultures and levels of urinary nitrate plus nitrite were suppressed by treatment with aminoguanidine (AG), a selective inhibitor of iNOS. The survival rates of AG-treated mice were significantly decreased by either lethal or sublethal S. aureusinfections. However, an effect of AG administration on bacterial growth was not observed in the spleens and kidneys of mice during either type of infection. Production of TNF-α and IFN-γ was not affected by AG treatment in vitro and in vivo. These results suggest that NO plays an important role in protection from lethality by the infection, but the protective role of NO in host resistance against S. aureusinfection was not proved. Moreover, our results show that TNF-α and IFN-γ regulate NO production while NO may not be involved in the regulation of the production of these cytokines during S. aureus infection.

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A Potential Protective Role of Platelets during Septic Shock Does Not Depend on Their Purinergic Receptors

Blood ◽

10.1182/blood.v128.22.2537.2537 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2537-2537 ◽

Cited By ~ 1

Author(s):

Beatrice Hechler ◽

Chloé Zimmermann ◽

Yannick Rabouel ◽

Stéphanie Magnenat ◽

Mélanie Burban ◽

...

Keyword(s):

Septic Shock ◽

Platelet Count ◽

Purinergic Receptors ◽

Plasma Concentrations ◽

Protective Role ◽

P2y12 Receptor ◽

Severe Thrombocytopenia ◽

P2y1 Receptor ◽

Tnf Α

Abstract Thrombocytopenia frequently occurs in septic shock patients and is associated with a worsened outcome. Experimental data indicate that platelets may have a protective role during sepsis. Our aims were to i) assess the potential protective role of platelets during septic shock and ii) evaluate the involvement of platelet P2Y1 and P2Y12 purinergic receptors. We used a model of polymicrobial-induced septic shock in mice by cecal ligation below the ileocecal valve and double puncture (CLP). The impact of moderate to severe thrombocytopenia was evaluated using mice deficient for the thrombopoietin receptor (Mpl-R-/-, 80% reduction in platelet count) and intravenous administration of a platelet specific rat anti-GPIbα monoclonal antibody (RAM.6, 2 mg/kg, 93% reduction in platelet count), respectively. To investigate the role of the P2Y12 receptor, WT mice were treated with clopidogrel, an irreversible inhibitor of the P2Y12 receptor, administered per os at 10 mg/kg, the day before and 2 h prior to surgery. Contribution of the P2Y1 receptor was evaluated using mice deficient for the P2Y1 receptor (P2Y1-/-). Mice underwent sham or CLP surgery (6 animals/group). Twenty hours post-surgery, blood and tissue samples were collected to evaluate critical parameters of septic shock. Mortality was recorded in a second group of animals. Twenty hours after CLP, mice with either normal or reduced platelet counts displayed signs of septic shock such as apathy, fur ruffling, conjunctivitis and diarrhea. Their mean arterial blood pressure (MAP) fell by 30% indicating systemic hypotension and organ failure characteristic of shock. Mpl-R-/- mice, displaying moderate thrombocytopenia, showed enhanced plasma concentrations of the pro-inflammatory cytokines TNF-α and IL-6, and of myeloperoxidase (MPO), indicating increased systemic inflammation relative to WT mice. These effects were more pronounced in RAM.6-treated mice displaying severe thrombocytopenia. Thrombin-antithrombin (TAT) complexes, reflecting in vivo thrombin generation, were enhanced in RAM.6-treated mice as compared to Mpl-R-/-mice or WT mice. Thrombocytopenia was also associated with increased plasma levels of aspartate aminotransferase (ASAT) relative to mice with normal platelet count, an effect also more pronounced in severely thrombocytopenic mice. These results indicate that depletion of platelets worsened organ injury during septic shock. Finally, severely thrombocytopenic mice succumbed more rapidly than control mice after CLP. Twenty hours after CLP, clopidogrel-treated mice and P2Y1-/- mice displayed signs of shock attested by a 30% decrease in MAP, similar to that observed in WT mice. Plasma concentrations of TNF-α, IL-6 and MPO were similarly increased in WT, clopidogrel-treated and P2Y1-/- mice. In addition, no differences in TAT levels were observed between the three groups of mice. Finally, the extent of liver damage, as evaluated by measurement of plasma ASAT levels, was similar between clopidogrel-treated mice, P2Y1-/-mice and WT mice. Overall, these results provide evidence for a beneficial role of platelets during experimental septic shock in mice. However, the platelet ADP receptors do not contribute to this effect, suggesting that anti-platelet therapy with P2Y12 receptor antagonists may not be beneficial in patients with septic shock. The mechanisms by which platelets modulate the host response to septic shock remain to be elucidated. Disclosures No relevant conflicts of interest to declare.

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