scholarly journals AB0109 THE ROLE OF CD70 IN THE DEVELOPMENT OF RHEUMATOID ARTHRITIS

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

Mechanistic Insights into Immunological Therapy for Targeting Diabetic Retinopathy

2021 ◽  
Vol 5 (3) ◽  
pp. 01-05
Author(s):  
Imteyaz Qamar
Keyword(s):  
Diabetic Retinopathy ◽  
Progressive Disease ◽  
Common Complication ◽  
Blood Retinal Barrier ◽  
Immunological Therapy ◽  
Tnf Α ◽  
Capillary Occlusion ◽  
Inflammatory Molecules ◽  
Inflammatory Effect

Diabetic retinopathy (DR) is a common complication amongst patients that have diabetes. It is a leading cause of blindness in middle age people. A large proportion of patients who have diabetes develop retinopathy. There are several immunological reasons associated with the pathophysiology of this disease. Role of several mediators that increase the oxidative stress and have a pro-inflammatory effect which leads to capillary occlusion and neovascularization (NV). Increased vasopermeability due to disruption of the blood-retinal barrier (BRB) leading to diabetic macular edema (DME). Immunotherapies utilise different compounds and target various inflammatory molecules like TNF-α and pathways such as PPARγ for treatment of this progressive disease. Inflammatory and pro-inflammatory pathways are found to have an essential role in promoting DR; therefore, targeting them provides a useful technique for curing DR.

scholarly journals Hypoxia increases KIAA1199/CEMIP expression and enhances cell migration in pancreatic cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takuya Oba ◽  
Norihiro Sato ◽  
Yasuhiro Adachi ◽  
Takao Amaike ◽  
Yuzan Kudo ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Expression ◽  
Hypoxia Inducible Factor ◽  
Ductal Adenocarcinoma ◽  
Rt Pcr ◽  
Transwell Migration Assay ◽  
Migration Assay ◽  
Hypoxic Conditions ◽  
Mrna And Protein Expression ◽  
Interfering Rna

AbstractPancreatic ductal adenocarcinoma (PDAC) is characterised by dense desmoplasia and hypoxic microenvironment. Our previous reports demonstrated that hyaluronan (HA), especially low-molecular-weight HA, provides a favourable microenvironment for PDAC progression. However, the effect of hypoxia on HA metabolism remains unknown. Using quantitative real-time RT-PCR and western blot analysis, we analysed the changes in the expression of HA-synthesizing enzymes (HAS2 and HAS3) and HA-degrading enzymes (HYAL1, KIAA1199/CEMIP) in PDAC cell lines under hypoxic conditions. Hypoxia increased the mRNA and protein expression of KIAA1199, whereas it decreased HYAL1 expression. The expression of HAS3 was increased and HAS2 remained unchanged in response to hypoxia. The effect of KIAA1199 on hypoxia-induced cell migration was determined using a transwell migration assay and small-interfering RNA (siRNA). Hypoxia enhanced the migratory ability of PDAC cells, which was inhibited by KIAA1199 knockdown. We also used immunohistochemistry to analyse the protein expression of hypoxia inducible factor (HIF) 1α and KIAA1199 in PDAC tissues. There was a significant immunohistochemically positive correlation between KIAA1199 and HIF1α. These findings suggest that hypoxia-induced KIAA1199 expression may contribute to enhanced motility in PDAC.

scholarly journals Multifaceted role of TNF-α during the pathogenesis of rheumatoid arthritis

2013 ◽  
Vol 04 (10) ◽  
pp. 937-940 ◽  
Author(s):  
Ramanjaneya V. R. Mula ◽  
Rangaiah Shashidharamurthy
Keyword(s):  
Rheumatoid Arthritis ◽  
Tnf Α

scholarly journals HIF-1α contributes to Ang II-induced inflammatory cytokine production in podocytes

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hao Huang ◽  
Yanqin Fan ◽  
Zhao Gao ◽  
Wei Wang ◽  
Ning Shao ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Inflammatory Factors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Inflammatory Injury ◽  
Tnf Α

Abstract Background Studies have indicated that changed expression of hypoxia-inducible factor-1α (HIF-1α) in epithelial cells from the kidney could affect the renal function in chronic kidney disease (CKD). As Angiotensin II (Ang II) is a critical active effector in the renin-angiotensin system (RAS) and was proved to be closely related to the inflammatory injury. Meanwhile, researchers found that Ang II could alter the expression of HIF-1α in the kidney. However, whether HIF-1α is involved in mediating Ang II-induced inflammatory injury in podocytes is not clear. Methods Ang II perfusion animal model were established to assess the potential role of HIF-1α in renal injury in vivo. Ang II stimulated podocytes to observe the corresponding between HIF-1α and inflammatory factors in vitro. Results The expression of inflammatory cytokines such as MCP-1 and TNF-α was increased in the glomeruli from rats treated with Ang II infusion compared with control rats. Increased HIF-1α expression in the glomeruli was also observed in Ang II-infused rats. In vitro, Ang II upregulated the expression of HIF-1α in podocytes. Furthermore, knockdown of HIF-1α by siRNA decreased the expression of MCP-1 and TNF-α. Moreover, HIF-1α siRNA significantly diminished the Ang II-induced overexpression of HIF-1α. Conclusion Collectively, our results suggest that HIF-1α participates in the inflammatory response process caused by Ang II and that downregulation of HIF-1α may be able to partially protect or reverse inflammatory injury in podocytes.

scholarly journals Role of cell migration in the pathogenesis of rheumatoid arthritis: in vivo studies in SCID mice transplanted with human synovial membrane

Reumatismo ◽  
2011 ◽  
Vol 54 (2) ◽  
Author(s):  
F. Ingegnoli ◽  
M. Blades ◽  
A. Manzo ◽  
S. Wahid ◽  
M. Perretti ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Migration ◽  
Synovial Membrane ◽  
Scid Mice ◽  
In Vivo Studies

scholarly journals Low Energy Shock Wave Therapy Inhibits Inflammatory Molecules and Suppresses Prostatic Pain and Hypersensitivity in a Capsaicin Induced Prostatitis Model in Rats

2019 ◽  
Vol 20 (19) ◽  
pp. 4777 ◽  
Author(s):  
Hung-Jen Wang ◽  
Pradeep Tyagi ◽  
Yu-Ming Chen ◽  
Michael B. Chancellor ◽  
Yao-Chi Chuang
Keyword(s):  
Shock Wave ◽  
Inflammatory Cells ◽  
Low Energy ◽  
Therapeutic Effects ◽  
Inflammatory Reactions ◽  
Caspase 1 ◽  
Tnf Α ◽  
Pain Reaction ◽  
Cox 2 ◽  
Inflammatory Molecules

The effect of low energy shock wave (LESW) therapy on the changes of inflammatory molecules and pain reaction was studied in a capsaicin (10 mM, 0.1 cc) induced prostatitis model in rats. Intraprostatic capsaicin injection induced a pain reaction, including closing of the eyes, hypolocomotion, and tactile allodynia, which effects were ameliorated by LESW treatment. LESW therapy (2Hz, energy flux density of 0.12 mJ/mm2) at 200 and 300 shocks significantly decreased capsaicin-induced inflammatory reactions, reflected by a reduction of tissue edema and inflammatory cells, COX-2 and TNF-α stained positive cells, however, the therapeutic effects were not observed at 100 shocks treated group. Capsaicin-induced IL-1β, COX-2, IL-6, caspase-1, and NGF upregulation on day 3 and 7, while NALP1 and TNF-α upregulation was observed on day 7. LESW significantly suppressed the expression of IL-1β, COX-2, caspase-1, NGF on day 3 and IL-1β, TNF-α, COX-2, NALP1, caspase-1, NGF expression on day 7 in a dose-dependent fashion. LESW has no significant effect on IL-6 expression. Intraprostatic capsaicin injection activates inflammatory molecules and induces prostatic pain and hypersensitivity, which effects were suppressed by LESW. These findings might be the potential mechanisms of LESW therapy for nonbacterial prostatitis in humans.

Role of the adipocyte-specific NF-κB activity in the regulation of IP-10 and T cell migration

2011 ◽  
Vol 300 (2) ◽  
pp. E304-E311 ◽  
Author(s):  
Patricia Krinninger ◽  
Cornelia Brunner ◽  
Pedro A. Ruiz ◽  
Elisabeth Schneider ◽  
Nikolaus Marx ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cell Migration ◽  
T Cell ◽  
Interferon Γ ◽  
Low Grade ◽  
Human Adipocytes ◽  
Migration Assay ◽  
T Cell Migration ◽  
Low Grade Inflammation

Infiltration of immune cells into adipose tissue plays a central role in the pathophysiology of obesity-associated low-grade inflammation. The aim of this study was to analyze the role of adipocyte NF-κB signaling in the regulation of the chemokine/adipokine interferon-γ-induced protein 10 kDa (IP-10) and adipocyte-mediated T cell migration. Therefore, the regulation of IP-10 was investigated in adipose tissue of male C57BL/6J mice, primary human and 3T3-L1 preadipocytes/adipocytes. To specifically block the NF-κB pathway, 3T3-L1 cells stably overexpressing a transdominant mutant of IκBα were generated, and the chemical NF-κB inhibitor Bay117082 was used. Adipocyte-mediated T cell migration was assessed by a migration assay. It could be shown that IP-10 expression was higher in mature adipocytes compared with preadipocytes. Induced IP-10 expression and secretion were completely blocked by an NF-κB inhibitor in 3T3-L1 and primary human adipocytes. Stable overexpression of a transdominant mutant of IκBα in 3T3-L1 adipocytes led to an inhibition of basal and stimulated IP-10 expression and secretion. T cell migration was induced by 3T3-L1 adipocyte-conditioned medium, and both basal and induced T cell migration was strongly inhibited by stable overexpression of a transdominant IκBα mutant. In addition, with the use of an anti-IP-10 antibody, a significant decrease of adipocyte-induced T cell migration was shown. In conclusion, in this study, we could demonstrate that the NF-κB pathway is essential for the regulation of IP-10 in 3T3-L1 and primary human adipocytes. Adipocytes rather than preadipocytes contribute to NF-κB-dependent IP-10 expression and secretion. Furthermore, NF-κB-dependent factors and especially IP-10 represent novel signals from adipocytes to induce T cell migration.

CHANGES THE CYTOKINE PROFILE AND CALCIUM-REGULATING HORMONES IN RHEUMATOID ARTHRITIS

2019 ◽  
Vol 64 (11) ◽  
pp. 673-676
Author(s):  
Asmaya Saftar Huseynova
Keyword(s):  
Rheumatoid Arthritis ◽  
Parathyroid Hormone ◽  
Bone Loss ◽  
Hypovitaminosis D ◽  
Serum Levels ◽  
Control Group ◽  
Tnf Α ◽  
High Production ◽  
Serological Variant

The aim was to study the level of some cytokines (İL-2, İL-6, İL-8 TNFα) and calcium regulating hormones (calcitonin, parathyroid hormone, 25 (OH) D) in the blood of patients with rheumatoid arthritis (RA) depending on rheumatoid factor (RF) and the assessment of the role of the revealed violations in the pathogenesis of bone loss in this pathology. For this purpose, 74 patients with RA (59 women, 15 men) aged from 27 to 71 were examined. On the basis of RF in the blood serum, the patients were divided into 2 groups: seronegative and seropositive RA. The control group included 16 healthy individuals (13 women, 3 men). The results obtained that the serological variant of RA affects the serum levels of proinflammatory cytokines and calcium-regulating hormones: more pronounced changes were found in seropositive RA. The high production of IL-2, IL-6, IL-8, TNF-α and parathyroid hormone detected in both groups of patients undoubtedly contributes to the mechanisms of bone loss in RA. In both groups we detected hypovitaminosis D. This results recommended to use this vitamin in the complex treatment of RA.

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

2008 ◽  
Vol 56 (7) ◽  
pp. 902-910 ◽  
Author(s):  
Stacy R. Oliver ◽  
Rebecca L. Flores ◽  
Andria M. Pontello ◽  
Jaime S. Rosa ◽  
Frank P. Zaldivar ◽  
...  
Keyword(s):  
Ketone Bodies ◽  
Cardiovascular Complications ◽  
Protective Role ◽  
Young Males ◽  
Tnf Superfamily ◽  
Blood Drawing ◽  
Tnf Α ◽  
Epidermal Growth ◽  
Glucose Lowering Effect

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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