Interleukin-1-like activities in synovial fluids of patients with rheumatoid arthritis and traumatic synovitis

1985 ◽  
Vol 5 (2) ◽  
pp. 79-82 ◽  
Author(s):  
K. Bendtzen ◽  
J. Petersen ◽  
J. Halkj�r-Kristensen ◽  
T. Ingemann-Hansen
Keyword(s):  
Rheumatoid Arthritis ◽  
Interleukin 1 ◽  
Synovial Fluids

scholarly journals AB0108 IRAK4 INHIBITION SUPPRESSES PROINFLAMMATORY CYTOKINE PRODUCTION FROM HUMAN MACROPHAGES STIMULATED WITH SYNOVIAL FLUID FROM RHEUMATOID ARTHRITIS PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1353.2-1353
Author(s):  
A. Yadon ◽  
D. Ruelas ◽  
G. Min-Oo ◽  
J. Taylor ◽  
M. R. Warr
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Signaling Pathways ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Interleukin 1 ◽  
Proinflammatory Cytokine Production ◽  
Human Macrophages ◽  
Percent Suppression

Background:Rheumatoid arthritis (RA) is characterized by chronic, uncontrolled joint inflammation and tissue destruction. Macrophages are thought to be key mediators in both the initiation and perpetuation of this pathology.1,2The RA synovium contains a complex inflammatory milieu that can stimulate macrophage-dependent production of proinflammatory cytokines through multiple signaling pathways.1,2Existing evidence indicates that toll-like receptors (TLRs) and interleukin-1 receptors (IL-1R) along with their agonists, damage-associated molecular patterns (DAMPs) and IL-1β, are highly expressed in RA joints and are important mediators of synovial macrophage activation and proinflammatory cytokine production.1-9IRAK4 (interleukin-1 receptor-associated kinase 4) is a serine/threonine kinase that facilitates TLR and IL-1R signaling in many cell types, including macrophages.10IRAK4 inhibition represents an opportunity to reduce proinflammatory cytokine production in the joints of patients with RA.Objectives:To investigate the effect of a highly selective IRAK4 inhibitor on proinflammatory cytokine production from human macrophages stimulated with synovial fluid from patients with RA.Methods:Primary human monocytes from 2 independent donors were differentiated for 6 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) to generate human monocyte-derived macrophages (hMDMs). hMDMs were then pretreated with an IRAK4 inhibitor for 1 hour and subsequently stimulated for 24 hours with RA synovial fluid from 5 patients. Culture supernatants were then assessed for secretion of proinflammatory cytokines by MesoScale Discovery.Results:RA synovial fluid stimulation of hMDMs resulted in the production of several proinflammatory cytokines, including IL-6, IL-8, and TNFα. Pretreatment of hMDMs with an IRAK4 inhibitor resulted in the dose-dependent inhibition of IL-6, IL-8, and TNFα production, with an average EC50± SD of 27 ± 31, 26 ± 41, and 28 ± 22 nM, respectively. Maximal percent suppression ± SD of IL-6, IL-8, and TNFα were 76 ± 8.8, 73 ± 15, and 77 ± 13, respectively. To evaluate the specific IRAK4-dependent signaling pathways mediating this response, hMDMs were pretreated with inhibitors of TLR4 (TAK242) and IL-1R (IL-1RA) prior to stimulation with RA synovial fluid. Both TAK242 and IL-1RA inhibited proinflammatory cytokine production. For TAK242, maximal percent suppression ± SD of IL-6, IL-8, and TNFα were 39 ± 25, 48 ± 24, and 50 ± 21, respectively. For IL-1RA maximal percent suppression ± SD of IL-6, IL-8, and TNFα were 18 ± 18, 20 ± 23, and 16 ± 18, respectively. The broad range of inhibition across each stimulation highlights the complexity and variability in the signaling pathways mediating proinflammatory cytokine production from hMDMs stimulated with RA synovial fluid, but demonstrates that RA synovial fluid can stimulate proinflammatory cytokine production in hMDMs, at least partly, through IRAK4-dependent pathways.Conclusion:This work demonstrates that IRAK4 inhibition can suppress proinflammatory cytokine production from macrophages stimulated with synovial fluid from patients with RA and supports a potential pathophysiological role for IRAK4 in perpetuating chronic inflammation in RA.References:[1]Smolen JS, et al.Nat Rev Dis Primers.2018;4:18001.[2]Udalova IA, et al.Nat Rev Rheumatol.2016;12(8):472-485.[3]Joosten LAB, et al.Nat Rev Rheumatol.2016;12(6):344-357.[4]Huang QQ, Pope RM.Curr Rheumatol Rep.2009;11(5):357-364.[5]Roh JS, Sohn DH.Immune Netw.2018;18(4):e27.[6]Sacre SM, et al.Am J Pathol.2007;170(2):518-525.[7]Ultaigh SNA, et al.Arthritis Res Ther.2011;13(1):R33.[8]Bottini N, Firestein GS.Nat Rev Rheumatol.2013;9(1):24-33.[9]Firestein GS, McInnes IB.Immunity.2017;46(2):183-196.[10]Janssens S, Beyaert R.Mol Cell.2003;11(2):293-302.Disclosure of Interests:Adam Yadon Employee of: Gilead, Debbie Ruelas Employee of: Gilead, Gundula Min-Oo Employee of: Gilead, James Taylor Employee of: Gilead, Matthew R. Warr Employee of: Gilead

scholarly journals Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

2020 ◽  
Vol 21 (4) ◽  
pp. 1340 ◽  
Author(s):  
Riko Nishimura ◽  
Kenji Hata ◽  
Yoshifumi Takahata ◽  
Tomohiko Murakami ◽  
Eriko Nakamura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcription Factors ◽  
Signaling Pathways ◽  
Genetic Disorder ◽  
Interleukin 1 ◽  
Genetic Diseases ◽  
Mtor Inhibitors ◽  
Joint Diseases ◽  
Ectopic Ossification ◽  
Parathyroid Hormone Related Protein

Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 million and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. Interleukin-1 β (IL-1β) leads to osteoarthritis through NF-ĸB, IκBζ, and the Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and tumor necrosis factor α (TNFα) play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), parathyroid hormone-related protein (PTHrP), and Indian hedgehog, play roles in regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling pathways cause genetic disorders in cartilage and skeletal tissues. Fibrodysplasia ossificans progressive, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. Mechanistic target of rapamycin kinase (mTOR) inhibitors can prevent ectopic ossification induced by ACVR1 mutations. C-type natriuretic peptide is currently the most promising therapy for achondroplasia and related autosomal genetic diseases that manifest severe dwarfism. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels has enlightened the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.

scholarly journals P5426Effects of inhibition of interleukin 1 and 6 activity on myocardial and vascular function compared with prednisolone in patients with rheumatoid arthritis

2018 ◽  
Vol 39 (suppl_1) ◽  
Author(s):  
I Ikonomidis ◽  
G Pavlidis ◽  
P Katsimbri ◽  
I Andreadou ◽  
H Triantafyllidi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Vascular Function ◽  
Interleukin 1

Interleukin-1 β gene polymorphisms in Egyptian patients with rheumatoid arthritis

2013 ◽  
Vol 23 (3) ◽  
pp. 689-694 ◽  
Author(s):  
Rania Kamal Darwish ◽  
Dalia Ibrahim Ramadan ◽  
Abeer Mohamed Mohy ◽  
Hala Ahmed Raafat ◽  
Hazem El-Sayed Abou Youssef ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Polymorphisms ◽  
Interleukin 1 ◽  
Egyptian Patients

scholarly journals Proinflammatory Soluble Interleukin-15 Receptor Alpha Is Increased in Rheumatoid Arthritis

Arthritis ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Ana Cecilia Machado Diaz ◽  
Araceli Chico Capote ◽  
Celia Aurora Arrieta Aguero ◽  
Yunier Rodríguez Alvarez ◽  
Diana García del Barco Herrera ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Reverse Signaling ◽  
Synovial Fluids ◽  
Inflammatory Processes ◽  
Membrane Bound ◽  
Interleukin 15 ◽  
Interleukin 15 Receptor Alpha ◽  
Pro Inflammatory Cytokines

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease in which many cytokines have been implicated. In particular, IL-15 is a cytokine involved in the inflammatory processes and bone loss. The aim of this study was to investigate the existence in synovial fluid of soluble IL-15Rα, a private receptor subunit for IL-15 which may act as an enhancer of IL-15-induced proinflammatory cytokines. Soluble IL-15Rα was quantified by a newly developed enzyme-linked immunosorbent assay (ELISA) in samples of synovial fluid from patients with RA and osteoarthritis (OA). The levels of IL-15Rα were significantly increased in RA patients compared to OA patients. Also, we studied the presence of membrane-bound IL-15 in cells from synovial fluids, another element necessary to induce pro-inflammatory cytokines through reverse signaling. Interestingly, we found high levels of IL-6 related to high levels of IL-15Rα in RA but not in OA. Thus, our results evidenced presence of IL-15Rα in synovial fluids and suggested that its pro-inflammatory effect could be related to induction of IL-6.

scholarly journals Study of IL-33 and IL-1R4 in Iraqi Rheumatoid Arthritis Female Patient's with and without Dyslipidemia Prone to Atherosclerosis

2019 ◽  
Vol 32 (1) ◽  
pp. 47
Author(s):  
Lara Ali Nazar ◽  
Eiman AA.` Abass
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatoid Factor ◽  
Erythrocyte Sedimentation Rate ◽  
Sedimentation Rate ◽  
Interleukin 1 ◽  
Control Group ◽  
Control Groups ◽  
Interleukin 33 ◽  
Erythrocyte Sedimentation ◽  
And Control

   This study is planned to find relationship between interleukin-33 (IL-33) with its receptor interleukin-1 receptor 4 (IL-1R4), and assurance IL-33/IL-1R4 proportion as biomarker to atherosclerosisin rheumatoid arthritis (RA) Iraqi females patients with and without dyslipidemia. This study was attempted at Baghdad Teaching Hospital included 60 females patients with RA that were isolated into: 30 patients with dyslipidemia(G2), 30 patients without dyslipidemia(G3) and 30 individual as control group (G1) .Patients were experiencing treatment by methortexiene medication, analyzed by rheumatoid factor(RF) and erythrocyte sedimentation rate( ESR) tests. All patients and control groups age ranged from (30-55) years. The results show an increase in ESR, RF, IL-33, and IL-1R4 levels. In addition to decrease in IL-33/IL-1R4 ratio in the two patients groups when contrasted and control group. The momentum examine inferred that the level of ESR, and  IL-33 in RA Iraqi females  patients with dyslipidemia were higher than that in RA Iraqi females patients without dyslipidemia, while the level of IL-33/IL-1R4 ratio in RA Iraqi females patients with dyslipidemia was lower than that in RA Iraqi females patients without dyslipidemia patients; in this manner the IL-33/IL-1R4 ratio may be used as a biomarker in diagnostic early porn to atherosclerosis in RA females patients with dyslipidemia

Sign in / Sign up

Export Citation Format

Share Document