scholarly journals The Significance of IL-36 Hyperactivation and IL-36R Targeting in Psoriasis

2019 ◽  
Vol 20 (13) ◽  
pp. 3318 ◽  
Author(s):  
Madonna ◽  
Girolomoni ◽  
Dinarello ◽  
Albanesi
Keyword(s):  
Cell Activation ◽  
Psoriatic Skin ◽  
T Helper ◽  
Endothelial Cell Activation ◽  
Pathological Angiogenesis ◽  
Immune Mediated ◽  
Th 17 ◽  
Tnf Α ◽  
Inflammatory Processes ◽  
Novel Therapeutic Strategies

Psoriasis is an immune-mediated inflammatory skin disease that involves mainly T helper (Th)17, Th1 and Th22 lymphocytes, which cause hyper-proliferation of the epidermis with aberrant differentiation of keratinocytes, and local production of chemokines and cytokines. These fuel a self-amplifying loop where these products act on T cells to perpetuate cutaneous inflammatory processes. Among the various inflammatory mediators involved, interleukin (IL)-36 cytokines are important for the recruitment and activation of neutrophils and Th17 cells in psoriatic skin. In particular, IL-36s induce chemokines and cytokines interfere with differentiation/cornification programs in the epidermis, as well as promote pathological angiogenesis and endothelial cell activation. IL-36 cytokines belong to the IL-1 family, and comprise IL-36α, IL-36β, and IL-36γ agonists as well as IL-36 receptor antagonist and IL-38 antagonists. IL-36 cytokines are up-regulated in psoriatic epidermis, and their expression is strongly induced by TNF-α and IL-17. Contrarily, IL-38 antagonist is downregulated, and its impaired expression may be relevant to the dysregulated inflammatory processes induced by IL-36. Here, we discuss on the pathogenic mechanisms leading to the altered balance of IL-36 agonists/antagonists and the significance of this dysregulation in psoriasis. Collection of the information will provide a theoretical basis for the development of novel therapeutic strategies based on IL-36 agonist/antagonist manipulation in psoriasis.

IL-23/Th17 Axis: A Potential Therapeutic Target of Psoriasis

2021 ◽  
Vol 13 ◽  
Author(s):  
Amit Sharma ◽  
Deepak Kumar Upadhyay ◽  
Ghanshyam Das Gupta ◽  
Raj Kumar Narang ◽  
Vineet Kumar Rai
Keyword(s):  
Therapeutic Target ◽  
T Helper Cells ◽  
T Helper ◽  
Potential Therapeutic Target ◽  
Immune Mediated ◽  
Th 17 ◽  
Tnf Α ◽  
Different Types ◽  
Th 1

: Psoriasis is an immune-mediated skin disease that leads to the initiation of abnormal production of inflammatory mediators and keratinocytes hyper-proliferation. Th-1 cell expressing cytokines such as IL-1β and TNF-α have been the important hallmarks in the management of psoriasis. However, investigations carried out in the previous few years underline the involvement of another subset of T helper cells, i.e. Th-17 in psoriasis exacerbation, and hence become the point of focus now. The immunopathogenesis of Th-17 is the result of the IL-23/Th-17 axis. It involves the release of IL-17 and IL-22 in response to the activated NF-kβ dependent activation of IL-23. The function of human Th-17 cells as well as the crucial role of IL-23/Th-17 axis in the exacerbation of psoriasis and treatment have been well explored. Therefore, considering IL-23/Th17 axis as a pertinent therapeutic target in immune driven disorders, extensive investigations are now highlighting the utility of biopharmaceuticals and/or biological agents acting on these targets. Here, we review the IL-23/Th-17 axis based therapeutic targets, different types of active moieties based on their source of availability and most useful USFDA approved Mabs targeting the IL-23/Th17 axis in psoriasis for a better understanding of the future possibilities in this area.

Direct Thrombin Inhibitors

2006 ◽  
Author(s):  
Richard C. Becker ◽  
Frederick A. Spencer
Keyword(s):  
Half Life ◽  
Cell Activation ◽  
Cellular Proliferation ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Endothelial Cell Activation ◽  
Heparin Induced Thrombocytopenia ◽  
Fibrinogen Binding ◽  
Inflammatory Processes ◽  
Repeated Dosing

The pivotal role of thrombin in all phases of coagulation, cellular proliferation, and cellular interactions involved centrally in inflammatory processes provides an attractive target for pharmacologic inhibition. The development of direct thrombin inhibitors has evolved rapidly to include both intravenous and oral preparations. Hirudin is extracted from the parapharyngeal gland of the medicinal leech Hirudo medicinalis. Several derivatives and recombinant preparations have been developed, including the most widely used agent lepirudin (Refludan). Hirudin binds to both the catalytic and fibrinogen-binding sites of thrombin and thus is considered a bivalent inhibitor. The plasma half-life of hirudin is 50 to 65 minutes, with a biologic half-life of 2 hours (Verstraete et al., 1993). The properties of heparin, hirudin, and bivalirudin are highlighted in Table 16.1. The predominant renal clearance of hirudin must be emphasized for safe clinical use. Hirudin forms a tight complex with thrombin, inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced platelet aggregation (Verstraete, 1997). These actions are independent of the presence of antithrombin, and also affect thrombin bound to fibrin. On the downside, the ability of thrombin to complex with thrombomodulin, activating protein C, is also inhibited. Hirudin does not bind to platelet factor , nor does it elicit antibodies that induce platelet and endothelial cell activation; thus, it can be safely administered to patients with heparin induced thrombocytopenia (HIT). Hirudin does have weak immunogenicity, so diminished (or rarely increased) responsiveness after repeated dosing is possible. The use of hirudin in the management of heparin-induced thrombocytopenia is discussed in Chapter 29.

scholarly journals TNF-α in T lymphocytes attenuates renal injury and fibrosis during nephrotoxic nephritis

2020 ◽  
Vol 318 (1) ◽  
pp. F107-F116 ◽  
Author(s):  
Yi Wen ◽  
Nathan P. Rudemiller ◽  
Jiandong Zhang ◽  
Taylor Robinette ◽  
Xiaohan Lu ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Renal Injury ◽  
Kidney Injury ◽  
Mrna Levels ◽  
T Helper ◽  
T Helper 17 ◽  
Immune Mediated ◽  
Tnf Α ◽  
Lymphocyte Responses

Nephrotoxic serum nephritis (NTN) models immune-mediated human glomerulonephritis and culminates in kidney inflammation and fibrosis, a process regulated by T lymphocytes. TNF-α is a key proinflammatory cytokine that contributes to diverse forms of renal injury. Therefore, we posited that TNF-α from T lymphocytes may contribute to NTN pathogenesis. Here, mice with T cell-specific deletion of TNF-α (TNF TKO) and wild-type (WT) control mice were subjected to the NTN model. At 14 days after NTN, kidney injury and fibrosis were increased in kidneys from TNF TKO mice compared with WT mice. PD1+CD4+ T cell numbers and mRNA levels of IL-17A were elevated in NTN kidneys of TNF TKO mice, suggesting that augmented local T helper 17 lymphocyte responses in the TNF TKO kidney may exaggerate renal injury and fibrosis. In turn, we found increased accumulation of neutrophils in TNF TKO kidneys during NTN. We conclude that TNF-α production in T lymphocytes mitigates NTN-induced kidney injury and fibrosis by inhibiting renal T helper 17 lymphocyte responses and infiltration of neutrophils.

scholarly journals Feline Infectious Peritonitis as a Systemic Inflammatory Disease: Contribution of Liver and Heart to the Pathogenesis

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1144 ◽  
Author(s):  
Alexandra J Malbon ◽  
Sonja Fonfara ◽  
Marina L Meli ◽  
Shelley Hahn ◽  
Herman Egberink ◽  
...  
Keyword(s):  
Inflammatory Disease ◽  
Clinicopathological Features ◽  
Cytokine Release ◽  
Feline Infectious Peritonitis ◽  
Immune Mediated ◽  
Tnf Α ◽  
Systemic Inflammatory Disease ◽  
Inflammatory State ◽  
Inflammatory Processes ◽  
Feline Coronavirus

Feline infectious peritonitis (FIP) is a fatal immune-mediated disease of cats, induced by feline coronavirus (FCoV). A combination of as yet poorly understood host and viral factors combine to cause a minority of FCoV-infected cats to develop FIP. Clinicopathological features include fever, vasculitis, and serositis, with or without effusions; all of which indicate a pro-inflammatory state with cytokine release. As a result, primary immune organs, as well as circulating leukocytes, have thus far been of most interest in previous studies to determine the likely sources of these cytokines. Results have suggested that these tissues alone may not be sufficient to induce the observed inflammation. The current study therefore focussed on the liver and heart, organs with a demonstrated ability to produce cytokines and therefore with huge potential to exacerbate inflammatory processes. The IL-12:IL-10 ratio, a marker of the immune system’s inflammatory balance, was skewed towards the pro-inflammatory IL-12 in the liver of cats with FIP. Both organs were found to upregulate mRNA expression of the inflammatory triad of cytokines IL-1β, IL-6, and TNF-α in FIP. This amplifying step may be one of the missing links in the pathogenesis of this enigmatic disease.

scholarly journals Concurrent Immune Suppression and Hyperinflammation in Patients With Community-Acquired Pneumonia

2020 ◽  
Vol 11 ◽  
Author(s):  
Xanthe Brands ◽  
Bastiaan W. Haak ◽  
Augustijn M. Klarenbeek ◽  
Natasja A. Otto ◽  
Daniël R. Faber ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Immune Suppression ◽  
Host Response ◽  
Cell Activation ◽  
Acute Infection ◽  
Community Acquired Pneumonia ◽  
Endothelial Cell Activation ◽  
Blood Leukocytes ◽  
Tnf Α ◽  
Neutrophil Degranulation

BackgroundThe nature and timing of the host immune response during infections remain uncertain and most knowledge is derived from critically ill sepsis patients. We aimed to test the hypothesis that community-acquired pneumonia (CAP) is associated with concurrent immune suppression and systemic inflammation.MethodsBlood was collected from 79 CAP patients within 24 h after hospitalization and 1 month after discharge; 42 age- and sex-matched subjects without acute infection served as controls. Blood leukocytes were stimulated with lipopolysaccharide (LPS) or Klebsiella pneumoniae, and cytokines were measured in supernatants. Fifteen plasma biomarkers reflective of key host response pathways were compared between CAP patients with the strongest immune suppression (lowest 25% blood leukocyte tumor necrosis factor (TNF)-α production in response to LPS) and those with the least immune suppression (highest 25% of LPS-induced TNF-α production).ResultsBlood leukocytes of CAP patients (relative to control subjects) showed a reduced capacity to release TNF-α, interleukin (IL)-1β, IL-6 and IL-10 upon stimulation with LPS or K. pneumoniae, with a concurrently enhanced ability to release the anti-inflammatory mediator IL-1 receptor antagonist, irrespective of the presence of sepsis (18.9% of cases). Low (relative to high) TNF-α producers displayed higher plasma levels of biomarkers reflecting systemic inflammation, neutrophil degranulation, endothelial cell activation, a disturbed vascular barrier function and coagulation activation.ConclusionCAP replicates a common feature of immune suppression in sepsis. The coexistence of immune suppression and hyperinflammation in CAP argues against the theory of two distinct phases during the host response to sepsis.

scholarly journals Effects of Ebola Virus Glycoproteins on Endothelial Cell Activation and Barrier Function

2005 ◽  
Vol 79 (16) ◽  
pp. 10442-10450 ◽  
Author(s):  
Victoria M. Wahl-Jensen ◽  
Tatiana A. Afanasieva ◽  
Jochen Seebach ◽  
Ute Ströher ◽  
Heinz Feldmann ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Barrier Function ◽  
Cell Activation ◽  
Matrix Protein ◽  
Ebola Virus ◽  
Endothelial Barrier ◽  
Endothelial Barrier Function ◽  
Endothelial Cell Activation ◽  
Tnf Α

ABSTRACT Ebola virus causes severe hemorrhagic fever with high mortality rates in humans and nonhuman primates. Vascular instability and dysregulation are disease-decisive symptoms during severe infection. While the transmembrane glycoprotein GP1,2 has been shown to cause endothelial cell destruction, the role of the soluble glycoproteins in pathogenesis is largely unknown; however, they are hypothesized to be of biological relevance in terms of target cell activation and/or increase of endothelial permeability. Here we show that virus-like particles (VLPs) consisting of the Ebola virus matrix protein VP40 and GP1,2 were able to activate endothelial cells and induce a decrease in barrier function as determined by impedance spectroscopy and hydraulic conductivity measurements. In contrast, the soluble glycoproteins sGP and Δ-peptide did not activate endothelial cells or change the endothelial barrier function. The VLP-induced decrease in barrier function was further enhanced by the cytokine tumor necrosis factor alpha (TNF-α), which is known to induce a long-lasting decrease in endothelial cell barrier function and is hypothesized to play a key role in Ebola virus pathogenesis. Surprisingly, sGP, but not Δ-peptide, induced a recovery of endothelial barrier function following treatment with TNF-α. Our results demonstrate that Ebola virus GP1,2 in its particle-associated form mediates endothelial cell activation and a decrease in endothelial cell barrier function. Furthermore, sGP, the major soluble glycoprotein of Ebola virus, seems to possess an anti-inflammatory role by protecting the endothelial cell barrier function.

scholarly journals Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation

2021 ◽  
Vol 118 (34) ◽  
pp. e2025813118
Author(s):  
Catherine Larochelle ◽  
Beatrice Wasser ◽  
Hélène Jamann ◽  
Julian T. Löffel ◽  
Qiao-Ling Cui ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Glutamate Release ◽  
Th2 Cells ◽  
Sequencing Analysis ◽  
T Helper ◽  
Triggered Release ◽  
T Helper 17 ◽  
Th 17 ◽  
Inflammatory Processes

T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes, and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate, which induced cell stress and changes in biosynthesis of cholesterol and lipids, as revealed by single-cell RNA-sequencing analysis. Finally, exposure to glutamate decreased myelination, whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities in MS.

In vitro endothelial cell activation and inflammatory responses in end-stage heart failure

2006 ◽  
Vol 101 (5) ◽  
pp. 1466-1473 ◽  
Author(s):  
Ginette S. Hoare ◽  
Emma J. Birks ◽  
Christopher Bowles ◽  
Nandor Marczin ◽  
Magdi H. Yacoub
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Activation ◽  
Endothelial Cell Activation ◽  
Tnf Α ◽  
Patients With Heart Failure ◽  
End Stage Heart Failure ◽  
End Stage ◽  
Iκbα Degradation

Background: vascular endothelial cell activation and dysfunction are observed in patients with severe heart failure and may contribute to systemic manifestations of this syndrome. It remains unknown whether inflammatory activation of these cells occurs in these patients because of increased circulating proinflammatory mediators. Aim: to determine whether the serum from patients with heart failure possesses a net proinflammatory bioactivity to active proinflammatory pathways in cultured endothelial cells. Methods: serum was obtained from stable patients with end-stage heart failure undergoing elective cardiac transplantation (Tx) and severely decompensated patients with heart failure requiring emergency left ventricular assist device (LVAD) implantation. Net proinflammatory bioactivity of serum was investigated by monitoring IκBα degradation and E-selectin expression in cultured human pulmonary artery endothelial cells (HPAEC) following incubation with serum samples. Serum cytokine concentrations were measured by ELISA and neutralizing antibodies were used to determine the role of specific factors in the observed bioactivity. Result: serum from both patient groups induced HPAEC IκBα degradation. Low basal HPAEC E-selectin expression significantly increased following treatment with Tx but not LVAD serum. Serum tumor necrosis factor-α (TNF-α) and IL-10 concentrations were higher in patients with LVAD than those with Tx, and soluble TNF-α receptor expression was high in both groups. Neither TNF-α nor IL-10 blocking experiments altered either bioassay result. Conclusion: activation of a specific profile of pro- and anti-inflammatory mediators is associated with heart failure resulting in HPAEC nuclear factor (NF)-κB activation. However, E-selectin expression is further regulated by unidentified factors. TNF-α is upregulated but appears to play no part in NFκB activation in these patients. These findings could have important therapeutic implications.

Inhibition of the endothelial cell activation by antithrombin in vitro

2004 ◽  
Vol 92 (12) ◽  
pp. 1420-1427 ◽  
Author(s):  
Mitsuhiro Uchiba ◽  
Christoph Kaun ◽  
Johann Wojta ◽  
Bernd Binder ◽  
Kenji Okajima
Keyword(s):  
Endothelial Cell ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cell Activation ◽  
Binding Protein ◽  
Inhibitory Effect ◽  
Inflammatory Activity ◽  
Endothelial Cell Activation ◽  
Tnf Α ◽  
Kinase A

SummaryWe examined whether antithrombin (AT) inhibits tumor necrosis factor (TNF)-α-induced endothelial cell activation to elucidate molecular mechanism(s) of the anti-inflammatory activity of AT. AT inhibited the increase in E-selectin expression in cultured human umbilical vein endothelial cells (HUVECs) stimulated with TNF-α. In contrast, chemically modified AT that lacks affinity for heparin did not. AT inhibited the TNF-αinduced interaction of NF-κB p65 with p300, a homologue of cAMP-responsive element binding protein (CREB)-binding protein (CBP). AT increased both intracellular levels of cAMP and binding of phosphorylated-CREB to DNA in HUVECs. Forskolin showed the inhibitory effect similar to that of AT and pretreatment of HUVECs with KT-5720, an inhibitor of protein kinase A, reversed the inhibitory effect of AT. These observations suggested that AT inhibited the TNF-α-induced increase in E-selectin expression in HUVECs by inhibiting the interaction of NF-κB with CBP/p300 through cAMP-dependent protein kinase A-induced CREB activation. This inhibitory activity of AT might depend on its binding to heparin-like substances on the endothelial cell. Such an inhibitory effect of AT on TNF-α-induced endothelial cell activation might at least partly contribute to its anti-inflammatory activity.

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