Release Of Several Chemokines Research Articles

Predictions based on inflammatory cytokine profiling of Egyptian COVID-19 with 2 potential therapeutic effects of certain marine-derived compounds

BackgroundsA worldwide coronavirus pandemic has affected many healthcare systems in 2019 (COVID-19). Following viral activation, cytokines and chemokines are released, causing inflammation and tissue death, particularly in the lungs, resulting in severe COVID-19 symptoms such as pneumonia and ARDS. COVID-19 induces the release of several chemokines and cytokines in different organs, such as the cardiovascular system and lungs. Research ideaCOVID-19 and its more severe effects, such as an elevated risk of death, are more common in patients with metabolic syndrome and the elderly. Cytokine storm and COVID-19 severity may be mitigated by immunomodulation targeting NF-κB activation in conjunction with TNF- α -inhibition. In severe cases of COVID-19, inhibiting the NF-κB/TNF- α, the pathway may be employed as a therapeutic option. Material and methodsThe study will elaborate on the Egyptian pattern for COVID-19 patients in the first part of our study. An Egyptian patient with COVID-19 inflammatory profiling will be discussed in the second part of this article using approved marine drugs selected to inhabit the significant inflammatory signals. A biomarker profiling study is currently being performed on Egyptian patients with SARS‐COV‐2. According to the severity of the infection, participants were divided into four groups. The First Group was non-infected with SARS-CoV-2 (Control, n = 16), the Second Group was non-intensive care patients (non-ICU, n = 16), the Third Group was intensive care patients (ICU, n = 16), and the Fourth Group was ICU with endotracheal intubation (ICU + EI, n = 16). To investigate COVID-19 inflammatory biomarkers for Egyptian patients, several inflammatory, oxidative, antioxidant, and anti-inflammatory biomarkers were measured. The following are examples of blood tests: CRP, Ferritin, D-dimer, TNF-α, IL-8, IL-6., IL-Ib, CD8, NF-κB, MDA, and total antioxidants. Results and discussionThe results of the current study revealed many logical findings, such as the elevation of CRP, Ferritin, D-dimer, TNF- α, CD8, IL-6, IL-, NF-κB, and MDA. Where a significant increase showed in ICU group results (23.05 ± 0.30, 2.35 ± 0.86, 433.4 ± 159.3, 26.67 ± 3.51, 7.52 ± 1.48, 7.49 ± 1.04, 5.76 ± 1.31, 7.41 ± 0.73) respectively, and also ICU group results (54.75 ± 3.44, 0.65 ± 0.13, 460.2 ± 121.42, 27.43 ± 2.52, 8.63 ± 2.68, 10.65 ± 2.75, 5.93 ± 1.4, 10.64 ± 0.86) respectively, as well as ICU + EI group results (117.63 ± 11.89, 1.22 ± 0.65, 918.8 ± 159.27, 26.68 ± 2.00, 6.68 ± 1.08, 11.68 ± 6.16, 6.23 ± 0.07, 22.41 ± 1.39),respectively.The elevation in laboratory biomarkers of cytokines storm in three infected groups with remarkable increases in the ICU + EI group was due to the elevation of oxidative stress and inflammatory storm molecules, which lead to highly inflammatory responses, specifically in severe patients of COVID-19. Another approach to be used in the current study is investigating new computational drug compounds for SARS‐COV‐2 protective agents from the marine environment. The results revealed that (Imatinib and Indinavir) had the highest affinity toward Inflammatory molecules and COVID-19 proteins (PDB ID: −7CZ4 and 7KJR), which may be used in the future as possible COVID-19 drug candidates. ConclusionThe investigated inflammatory biomarkers in Egyptian COVID-19 patients showed a strong correlation between IL6, TNF-α, NF-κB, CRB, DHL, and ferritin as COVID-19 biomarkers and determined the severity of the infection. Also, the oxidative /antioxidant showed good biomarkers for infection recovery and progression of the patients.

Abstract P082: Exposure To Excess Albumin Causes Inflammatory Activation Of The Proximal Tubule.

In previous studies, we used chronic servo control experiments to show that renal inflammation is a secondary event in salt-sensitive hypertension, with pressure amplifying renal immune cell infiltration in Dahl salt-sensitive (SS) rats. In contrast, albuminuria occurs early in the development of hypertension and facilitates its progression. In this study, we tested the hypothesis that albuminuria causes release of pro-inflammatory cytokines in the proximal tubule, which in turn may initiate renal inflammation.We exposed the apical membrane of human proximal tubule cell monolayers (RPTEC-TERT1) to human serum albumin (HSA, 10 mg/ml, n=8) for 24 and 48hrs. Control cells were kept in standard media without HSA (n=8). The concentrations of 47 cytokines were measured in the basolateral (BM) and apical (AM) media using Luminex assays. After 24hrs we found that 18 cytokines were significantly higher in the BM and 14 in the AM relative to controls. At 48hrs, 17 cytokines were significantly higher in the BM and 15 in the AM. Notably, we found significant increases in basolateral release of several chemokines, including CCL2 (24hrs: 6.1±0.9 vs. 40.6±8.9, 48hrs: 20.1±4.5 vs. 85.8±15.6 pg/mg), CXCL1 (24hrs: 1.3±0.3 vs. 39.5±12.2, 48hrs: 3.4±1.1 vs. 94.2±41.4 pg/mg), and IL-8 (24hrs: 1.3±0.4 vs. 11.6±3.7, 48hrs: 2.1±0.5 vs. 10.1±3 pg/mg). We propose that HSA-induced chemokine secretion facilitates immune cell recruitment and the initiation of renal inflammation. To track the progression of albuminuria and proximal tubule injury in SS rats we performed daily urine collections in rats fed either a high-salt (HS, 4.0% NaCl, n=6) or a control-salt (CS, 0.4% NaCl, n=5) diet for 7-days. In SS rats fed HS, albuminuria preceded proximal tubule injury. Urinary albumin was elevated after 2-days of HS (22.6±6.5 vs. 61.1±18.7 mg/day) whereas Kidney Injury Molecule-1 (KIM-1) was increased after 5-days of HS (15.5±1.5 vs. 31.3±5.6 ng/day).To conclude, in vitro exposure to excess albumin causes significant increases in the levels of multiple cytokines involved in the initiation of inflammation. In SS rats fed HS, albuminuria precedes proximal tubule injury. Together these data suggest that albuminuria may facilitate hypertension through the initiation of renal inflammation.

Toll-Like Receptors 2 and 4 Modulate Pulmonary Inflammation and Host Factors Mediated by Outer Membrane Vesicles Derived from Acinetobacter baumannii.

Pneumonia due to Gram-negative bacteria is associated with high mortality. Acinetobacter baumannii is a Gram-negative bacterium that is associated with hospital-acquired and ventilator-associated pneumonia. Bacteria have been described to release outer membrane vesicles (OMVs) that are capable of mediating systemic inflammation. The mechanism by which A. baumannii OMVs mediate inflammation is not fully defined. We sought to investigate the roles that Toll-like receptors (TLRs) play in A. baumannii OMV-mediated pulmonary inflammation. We isolated OMVs from A. baumannii cultures and intranasally introduced the OMVs into mice. Intranasal introduction of A. baumannii OMVs mediated pulmonary inflammation, which is associated with neutrophil recruitment and weight loss. In addition, A. baumannii OMVs increased the release of several chemokines and cytokines in the mouse lungs. The proinflammatory responses were partially inhibited in TLR2- and TLR4-deficient mice compared to those of wild-type mice. This study highlights the important roles of TLRs in A. baumannii OMV-induced pulmonary inflammation in vivo.

The Ischemic Disease: A Joke Where There's Nothing to Be Gained

Abstract 5198This study explored the hypothesis that the ischemic disease (ID) is associated with systemic alterations of the blood coagulation system: platelet activation (sCD40L: determined by ELISA) and release of various proteins (CRP: determined by nephelometry, IL-6: determined by ELISA).Plasma concentration of these factors were higher in patients with ischemic disease: sCD40L (ID: 724. 2 +/− 58. 4 vs controls 212 +/− 8. 6 pg/ml; p<0001), CRP (ID: 5. 76+/−1. 8 vs controls 2. 54 +/− 0. 3g/l; p<001), IL-6 (ID: 6. 36 +/− 1. 32 vs controls 2. 02 +/− 064 pg/ml; p<001).Platelet activation predicts the risk of ischemic events, in fact CD40L binds and activates alfa IIb/beta 3, and increases PMC (platelet – monocyte complexes), and PDMP (platelet derived microparticle), it also promotes the release of several chemokines (FP4, RANTES, CxCL, ENA 78, NAP-2) that may play an important role in plaque destabilization; high levels of CD40L predict cardiovascular risk of death or myocardial infarction, or stroke within 8 to 12 month in patients with asyntomatic low grade stenosis (carotid or coronary).Several data suggest that CRP has a prognostic value in patients with negative troponin and it is predictive for the development of CAD and refractory ischemic disease, plaque destabilization, and future adverse events, or for the development of severe disease.IL-6 was strongly associated with markers of inflammation (CRP, fibrinogen, white cells count), plasma viscosity, elevated markers of coagulation (fibrin, D-Dimer, FVIII, FIX); moreover IL-6 is associated with insulin resistance, and its levels are high in metabolic syndrome; it is significantly correlated with age, BMI, white cell count; IL-6 increases dendritic platelet forms and acts synergistically with thrombopoietin and stem-cell factor in stimulating megakaryocytopoiesis.Although it has been controversial, IL-6, PCR, and CD40L appear now to be very promising for quantifying the degree of ischemic disease and to monitor or to identify the efficacy and the response to the therapy. Disclosures:No relevant conflicts of interest to declare.

S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures

Sphingosine-1-phosphate receptors (S1PRs) are drug targets for the compound FTY720, which is the first oral therapy developed for treatment of relapsing-remitting multiple sclerosis. S1PRs play a variety of functional roles in the differentiation, proliferation, survival and/or migration of neurons and glia. In this study, rat organotypic cerebellar slice cultures were used to assess whether S1PRs play a role in demyelination induced by lysolecithin (LPC). The data demonstrated that FTY720 and SEW2871 (a S1P1R-specific agonist) inhibited LPC-induced demyelination as assessed by myelin basic protein (MBP) immunofluorescence. Treatment with both drugs for 48 h also induced an increase in S1P1R expression in astrocytes. Moreover, FTY720 and SEW2871 inhibited the release of several chemokines in conditions of LPC-induced demyelination, including LIX (CXCL5), MIP-1alpha, and MIP-3alpha. Taken together, the data suggest that activation of S1P1Rs prevents LPC-induced demyelination via a mechanism involving a reduction of chemotactic chemokine release. The study supports the concept that FTY720 attenuates demyelination by not only preventing S1PR-mediated T cell migration into the CNS but also by limiting cytokine communication between cells of the immune system and the CNS.

Biodegradable chitosan particles induce chemokine release and negligible arginase-1 activity compared to IL-4 in murine bone marrow-derived macrophages

Alternatively activated macrophages have been implicated in the therapeutic activity of biodegradable chitosan on wound healing, however, the mechanisms of phenotypic differentiation are still unclear . In vitro, macrophages stimulated with high doses of chitosan (⩾500 μg/mL) were reported to produce low-level markers associated with alternative activation (arginase-1) as well as classical activation (nitric oxide), and to undergo apoptosis. In this study, we tested the hypothesis that 40 kDa biodegradable chitosan (5–500 μg/mL) is sufficient to polarize mouse bone marrow-derived macrophages (BMDM) in vitro to an alternatively activated phenotype. Control cultures were stimulated with IL-4 (alternative activation), IFN-γ/LPS (classical activation), 1 μm diameter latex beads (phagocytosis), or left untreated. After 48 h of in vitro exposure, BMDM phagocytosed fluorescent chitosan particles or latex beads, and remained viable and metabolically active, although some cells detached with increasing chitosan and latex bead dosage. Arginase-1 was over 100-fold more strongly induced by IL-4 than by chitosan, which induced only sporadic and weak arginase-1 activity over untreated BMDM, and no nitric oxide. IFN-γ/LPS stimulated nitric oxide production and arginase-1 activity and high concentrations of inflammatory cytokines (IL-6, IL-1β, TNF-α, MIP-1α/MIP-1β), while latex beads stimulated nitric oxide and not arginase-1 activity. Chitosan or latex bead exposure, but not IL-4, tended to promote the release of several chemokines (MIP-1α/β, GM-CSF, RANTES, IL-1β), while all treatments promoted MCP-1 release. These data show that chitosan phagocytosis is not sufficient to polarize BMDM to the alternative or the classical pathway, suggesting that biodegradable chitosan elicits alternatively activated macrophages in vivo through indirect mechanisms.

The Crosstalk Between the Matrix Metalloprotease System and the Chemokine Network in Acute Myeloid Leukemia

Matrix metalloproteinases (MMPs) comprise a large family of zinc-dependent endopeptidases, which are best known for their ability to degrade essentially all components of the extracellular matrix (ECM). By breaking down ECM, MMPs may remove physical barriers, thus allowing cells to migrate and potentially invade other tissues. Recent evidence, however, shows that the proteolytic activities of MMPs also affect several fundamental physiological processes. Primary human acute myeloid leukemia (AML) cells often show constitutive release of several MMPs and chemokines, and there seems to be a crosstalk between the MMP system and the chemokine network. Firstly, the nuclear factor-κB (NF-κB) system represents a common regulator at the transcriptional level both for MMPs (e.g. MMP-1 and MMP-9) and for the constitutive release of several chemokines (CCL2-4/CXCL1/8) by primary human AML cells. Secondly, the crosstalk at the molecular level probably includes MMP-mediated structural alteration and activation of constitutively released chemokines involved in AML cell migration (e.g. CXCL12) and stimulation of bone marrow angiogenesis (e.g. CXCL8). Thirdly, at a functional level the two systems interact because the chemokine network plays a role in similar physiological processes as the MMPs, including AML cell proliferation and migration and local regulation of angiogenesis. Both the chemokine system and MMPs are currently being evaluated as targets in anti-angiogenesis/cancer therapy and may also have potential therapeutic implications in AML. This review introduces the different members of the MMP family and describes their interactions with the chemokine network and the possible involvement of MMPs together with chemokines in leukemogenesis and chemosensitivity in AML.

The protein kinase C agonist PEP005 increases NF‐κB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells

Acute myeloid leukaemia (AML) cells show constitutive release of several chemokines that occurs in three major clusters: (I) chemokine (C-C motif) ligand (CCL)2-4/chemokine (C-X-C motif) ligand (CXCL)1/8, (II) CCL5/CXCL9-11 and (III) CCL13/17/22/24/CXCL5. Ingenol-3-angelate (PEP005) is an activator of protein kinase C and has antileukaemic and immunostimulatory effects in AML. We investigated primary AML cells derived from 35 unselected patients and determined that PEP005 caused a dose-dependent increase in the release of chemokines from clusters I and II, including several T cell chemotactic chemokines. The release of granulocyte-macrophage colony-stimulating factor and hepatocyte growth factor was also increased. CCL2-4/CXCL1/8 release correlated with nuclear factor (NF)-kappaB expression in untreated AML cells, and PEP005-induced chemokine production was associated with further increases in the expression of the NF-kappaB subunits p50, p52 and p65. Increased DNA binding of NF-kappaB was observed during exposure to PEP005, and the specific NF-kappaB inhibitor BMS-345541 reduced constitutive chemokine release even in the presence of PEP005. Finally, PEP005 decreased expression of stem cell markers (CD117, CXCR4) and increased lineage-associated CD11b and CD14 expression. To conclude, PEP005 has a unique functional pharmacological profile in human AML. Previous studies have described proapoptotic and T cell stimulatory effects and the present study describes additional T cell chemotactic and differentiation-inducing effects.

Bone marrow-derived mesenchymal stem cells for treatment of heart failure: is it all paracrine actions and immunomodulation?

Despite significant advances in medical and surgical management of heart failure, mostly of ischaemic origin, the mortality and morbidity associated with it continue to be high. Pluripotent stem cells are being evaluated for treatment of heart failure. Bone marrow-derived mesenchymal stem cells (MSCs) have been extensively studied. Emerging evidence suggests that locally delivered MSCs can lead to an improvement in ventricular function, but the cellular and molecular mechanisms involved remain unclear. Myocardial regeneration, as proposed by many researchers as the underlying mechanism, has failed to convince the scientific community. Recently some authors have ascribed improvement in ventricular function to paracrine actions of MSCs.A lot has been written about the host immune response triggered by embryonic stem cells and the consequent need for immunosuppression. Not enough work has been done on immune interactions involving allogeneic bone marrow cells. Full potential of stem cell therapy can be realised only when we are able to use allogeneic cells. The potential use of MSCs in cellular therapy has recently prompted researchers to look into their interaction with the host immune response. MSCs have immunomodulatory properties. They cause suppression of proliferation of alloreactive T cells in a dose-dependent manner.Tissue injury causes inflammation and release of several chemokines, cytokines and growth factors. They can cause recruitment of bone marrow-derived MSCs to the injured area. We review the literature on paracrine actions and immune interactions of allogeneic MSCs.

Disruption of E-Cadherin-Mediated Adhesion Induces a Functionally Distinct Pathway of Dendritic Cell Maturation

The maturation of dendritic cells (DCs) after exposure to microbial products or inflammatory mediators plays a critical role in initiating the immune response. We found that maturation can also occur under steady-state conditions, triggered by alterations in E-cadherin-mediated DC-DC adhesion. Selective disruption of these interactions induced the typical features of DC maturation including the upregulation of costimulatory molecules, MHC class II, and chemokine receptors. These events were triggered at least in part by activation of the beta-catenin pathway. However, unlike maturation induced by microbial products, E-cadherin-stimulated DCs failed to release immunostimulatory cytokines, exhibiting an entirely different transcriptional profile. As a result, E-cadherin-stimulated DCs elicited an entirely different T cell response in vivo, generating T cells with a regulatory as opposed to an effector phenotype. These DCs induced tolerance in vivo and may thus contribute to the elusive steady-state "tolerogenic DCs."

Cytokine levels and inflammatory responses in developing late-phase allergic reactions in the skin

Background: Cytokines could play roles in the attraction of leukocytes into sites of IgE-mediated late-phase reactions (LPR) or in the activation of such cells at the sites. Previous studies found increased release of IL-6, IL-1, and granulocyte-macrophage colony–stimulating factor into skin chambers overlying allergen-challenged sites, mainly after 6 hours when LPR are already well-developed. Objective: To compare levels of several cytokines with inflammatory responses in skin chambers overlying developing LPRs. Methods: Skin chambers were appended to denuded blister bases in 15 sensitive subjects, then challenged over a 5-hour period with pollen allergens (Ag) or buffer control (B). Levels of several chemotactic cytokines, eosinophil cationic product (released from eosinophils), and lactoferrin (released from neutrophils) were measured and leukocyte accumulation was assessed. Results: Levels of the chemokines IL-8, RANTES, and monocyte chemotactic protein-1 (but not IL-1, IL-6, or granulocyte-macrophage colony–stimulating factor) were significantly higher at Ag-challenge sites than at B-challenge sites. IL-5 was not detected. In individual chamber fluids at Ag-challenge sites, (1) IL-8 levels correlated strongly with levels of lactoferrin but not with eosinophil cationic protein levels; (2) RANTES levels correlated with numbers of eosinophils but not with eosinophil cationic protein levels; and (3) levels of monocyte chemotactic protein-1 correlated weakly with histamine released after the first hour. Conclusions: During LPRs developing during the first 5 hours of Ag challenge, there is increased local release of several chemokines, which could play roles in the observed attraction and subsequent activation of leukocytes and continued histamine release observed at such sites. (J Allergy Clin Immunol 1997;100:104-9.)