NF-κB Mediates Cartilage Degradation Induced by Trauma Injury and Interleukin-1

2013 ◽  
Author(s):  
Meghana Kashyap ◽  
Kristen T. Carter ◽  
Brent C. Sauer ◽  
Christopher T. Chen
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Cartilage Degradation ◽  
Synovial Joint ◽  
Chondrocyte Death ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Trauma Injury ◽  
High Level ◽  
Impact Injury

Chondrocyte death, induced by impact injury (necrosis) and/or apoptotic inducers such as cytokines, and high level of nitric oxide, is important for the development of post-traumatic arthritis (PTA) [1–3]. The upregulation of pro-inflammatory cytokines, such as interleukin −1 (IL-1) and Tumor necrosis factor (TNF) α, is known to mediate cartilage degradation in inflammatory diseases and after trauma injury [1,2, 6–9]. IL-1 induces the degradation of proteoglycan (PG) in cartilage through NF-κB and Mitogen-activated protein kinases (MAPK: p38, ERK and JNK) pathways [1,2,6]. IL-1 is highly upregulated in synovial joint after impact injury, but the role of IL-1 induced chondrocyte death and matrix/PG degradation in injured cartilage is not completely clear.

Load Down-Regulates TNF-Alpha Induced Cartilage Degradation in Part Through NF-KB and P38 Pathways

2007 ◽  
Author(s):  
Valerie M. Wolfe ◽  
Seonghun Park ◽  
Marjana Tomic ◽  
Peter A. Torzilli ◽  
C. T. Christopher Chen
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Tensile Load ◽  
Cartilage Degradation ◽  
Acute Injury ◽  
Cyclic Compression ◽  
Tnf Α ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

Pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), can induce cartilage degradation after acute injury or in inflammatory diseases [1,2,3,7]. The degradative events are coordinated through the elevation and activation of two classes of enzymes, namely matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS-4 and −5) [1,6]. Prior studies suggested that pro-inflammatory responses induced by IL-1β can be inhibited by tensile load [2] and more recently by cyclic compression [8]. It is, however, not clear whether load affects other cytokines, such as TNF-α. TNF-α is known to bind its receptor (TNFR1) to cause a cascade that ends with degradation of an inhibitor, IκBα, and release of the transcription factor NF-κB [3]. The actions of TNF-α are also known to be affected by at least three NF-κB independent pathways including the p38, ERK, and JNK pathways [4]. The objective of this study was to determine whether cyclic compression could affect TNF-α induced cartilage degradation and to determine the roles of p38, ERK, and JNK pathways in TNF-induced cartilage degradation. We hypothesized that cyclic loading would inhibit the degradative effects caused by TNF-α.

TNF-α and interleukin 1 activate gastrin gene expression via MAPK- and PKC-dependent mechanisms

2001 ◽  
Vol 281 (6) ◽  
pp. G1405-G1412 ◽  
Author(s):  
T. Suzuki ◽  
E. Grand ◽  
C. Bowman ◽  
J. L. Merchant ◽  
A. Todisco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
G Cells ◽  
Kinase C ◽  
Tnf Α ◽  
Mitogen Activated Protein

Helicobacter pyloriand proinflammatory cytokines have a direct stimulatory effect on gastrin release from isolated G cells, but little is known about the mechanism by which these factors regulate gastrin gene expression. We explored whether tumor necrosis factor (TNF)-α and interleukin (IL)-1 directly regulate gastrin gene expression and, if so, by what mechanism. TNF-α and IL-1 significantly increased gastrin mRNA in canine G cells to 181 ± 18% and 187 ± 28% of control, respectively, after 24 h of treatment. TNF-α and IL-1 stimulated gastrin promoter activity to a maximal level of 285 ± 12% and 415 ± 26% of control. PD-98059 (a mitogen-activated protein kinase kinase inhibitor), SB-202190 (a p38 kinase inhibitor), and GF-109203 (a protein kinase C inhibitor) inhibited the stimulatory action of both cytokines on the gastrin promoter. In conclusion, both cytokines can directly regulate gastrin gene expression via a mitogen-activated protein kinase- and protein kinase C-dependent mechanism. These data suggest that TNF-α and IL-1 may play a direct role in Helicobacter pylori-induced hypergastrinemia.

The Role of Oxidative Stress, Inflammation, and Advanced Glycation End Product in Skin Manifestations of Diabetes Mellitus

2021 ◽  
Vol 17 ◽  
Author(s):  
Lili Legiawati
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Adhesion Molecule ◽  
Intercellular Adhesion Molecule ◽  
Skin Disorders ◽  
Intercellular Adhesion Molecule 1 ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
High Level ◽  
Factor Α

: Diabetes mellitus is a metabolic disorder caused by an increase in insulin resistance, a decrease in insulin production, or both of them, resulting in a high level of blood glucose or hyperglycemia. An uncontrolled state of DM may cause complications, namely skin disorder. One or more skin disorders are found amongst 74% of T2DM patients, with the highest percentage is dry skin (47%), followed by infection (10%), diabetic hand (5%), hair loss and diabetic dermopathy (each 4%). In DM, the state of hyperglycemia and production of advanced glycaemic end-products (AGEs) profoundly impact skin changes. In the pathological pathway, AGEs induce oxidative stress and inflammation. Nonetheless, AGEs level is higher in T2DM patients compared to non-T2DM people. This is caused by hyperglycemia and oxidative stress. Binding between AGEs and receptor of AGEs (RAGE) promotes pathway of oxidative stress and inflammation cascade via mitogen-activated protein kinases (MAPK), nuclear factor-k-light-chain-enhancer of activated β cells (NF-kβ), interleukin- 6 (IL-6), tumor necrosis factor-α (TNF-α), expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 2 (VCAM-2) pathway which furtherly effectuates DM complication including skin disorders.

scholarly journals Coordinate Regulation of IκB Kinases by Mitogen-Activated Protein Kinase Kinase Kinase 1 and NF-κB-Inducing Kinase

1998 ◽  
Vol 18 (12) ◽  
pp. 7336-7343 ◽  
Author(s):  
Shino Nemoto ◽  
Joseph A. DiDonato ◽  
Anning Lin
Keyword(s):  
Protein Kinase ◽  
Interleukin 1 ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Dominant Negative Mutant ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ikk Complex ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

ABSTRACT IκB kinases (IKKα and IKKβ) are key components of the IKK complex that mediates activation of the transcription factor NF-κB in response to extracellular stimuli such as inflammatory cytokines, viral and bacterial infection, and UV irradiation. Although NF-κB-inducing kinase (NIK) interacts with and activates the IKKs, the upstream kinases for the IKKs still remain obscure. We identified mitogen-activated protein kinase kinase kinase 1 (MEKK1) as an immediate upstream kinase of the IKK complex. MEKK1 is activated by tumor necrosis factor alpha (TNF-α) and interleukin-1 and can potentiate the stimulatory effect of TNF-α on IKK and NF-κB activation. The dominant negative mutant of MEKK1, on the other hand, partially blocks activation of IKK by TNF-α. MEKK1 interacts with and stimulates the activities of both IKKα and IKKβ in transfected HeLa and COS-1 cells and directly phosphorylates the IKKs in vitro. Furthermore, MEKK1 appears to act in parallel to NIK, leading to synergistic activation of the IKK complex. The formation of the MEKK1-IKK complex versus the NIK-IKK complex may provide a molecular basis for regulation of the IKK complex by various extracellular signals.

scholarly journals A Novel Small-Molecule Inhibitor of Endosomal TLRs Reduces Inflammation and Alleviates Autoimmune Disease Symptoms in Murine Models

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1648
Author(s):  
Mahesh Chandra Patra ◽  
Asma Achek ◽  
Gi-Young Kim ◽  
Suresh Panneerselvam ◽  
Hyeon-Jun Shin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Small Molecule ◽  
Lupus Erythematosus ◽  
Inflammatory Diseases ◽  
Poly I:C ◽  
Cpg Oligodeoxynucleotide ◽  
Molecule Inhibitor ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Α

Toll-like receptors (TLRs) play a fundamental role in the inflammatory response against invading pathogens. However, the dysregulation of TLR-signaling pathways is implicated in several autoimmune/inflammatory diseases. Here, we show that a novel small molecule TLR-inhibitor (TAC5) and its derivatives TAC5-a, TAC5-c, TAC5-d, and TAC5-e predominantly antagonized poly(I:C) (TLR3)-, imiquimod (TLR7)-, TL8-506 (TLR8)-, and CpG-oligodeoxynucleotide (TLR9)-induced signaling pathways. TAC5 and TAC5-a significantly hindered the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), reduced the phosphorylation of mitogen-activated protein kinases, and inhibited the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6. Besides, TAC5-a prevented the progression of psoriasis and systemic lupus erythematosus (SLE) in mice. Interestingly, TAC5 and TAC5-a did not affect Pam3CSK4 (TLR1/2)-, FSL-1 (TLR2/6)-, or lipopolysaccharide (TLR4)-induced TNF-α secretion, indicating their specificity towards endosomal TLRs (TLR3/7/8/9). Collectively, our data suggest that the TAC5 series of compounds are potential candidates for treating autoimmune diseases such as psoriasis or SLE.

scholarly journals Could Polyphenols Help in the Control of Rheumatoid Arthritis?

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1589 ◽  
Author(s):  
Sung ◽  
Kwon ◽  
Um ◽  
Kim
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Diseases ◽  
Mitogen Activated Protein Kinase ◽  
Bone Damage ◽  
Autoimmune Inflammatory Disease ◽  
Novel Drugs ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Α ◽  
Therapeutic Alternatives

Rheumatoid arthritis (RA) is a chronic, systemic, joint-invading, autoimmune inflammatory disease, which causes joint cartilage breakdown and bone damage, resulting in functional impairment and deformation of the joints. The percentage of RA patients has been rising and RA represents a substantial burden for patients around the world. Despite the development of many RA therapies, because of the side effects and low effectiveness of conventional drugs, patients still need and researchers are seeking new therapeutic alternatives. Polyphenols extracted from natural products are effective on several inflammatory diseases, including RA. In this review polyphenols are classified into four types: flavonoids, phenolic acids, stilbenes and others, among which mainly flavonoids are discussed. Researchers have reported that anti-RA efficacies of polyphenols are based mainly on three mechanisms: their anti-inflammatory, antioxidant and apoptotic properties. The main RA factors modified by polyphenols are mitogen-activated protein kinase (MAPK), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), nuclear factor κ light chain enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinases (JNK). Polyphenols could be potent alternative RA therapies and sources for novel drugs for RA by affecting its key mechanisms.

scholarly journals AntimiR-30b Inhibits TNF-α Mediated Apoptosis and Attenuated Cartilage Degradation through Enhancing Autophagy

2016 ◽  
Vol 40 (5) ◽  
pp. 883-894 ◽  
Author(s):  
Zhe Chen ◽  
Tao Jin ◽  
Yong Lu
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Direct Interaction ◽  
Cartilage Degradation ◽  
Protective Role ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Tnf Α ◽  
Ecm Degradation ◽  
Induced Apoptosis

Objective: Cell death plays an important role in the pathology associated with inflammatory diseases such as osteoarthritis. It has been reported that autophagy can protect cells against tumour necrosis factor-α (TNF-α)-induced apoptosis. This study aimed to determine the potential role of microRNA-30b (miR-30b) in TNF-α-induced apoptosis, autophagy and differentiation in the chondrogenic ADTC5 cell line. Methods: To analyse the effect of TNF-α on the viability of ADTC5 cells, cell counting kit-8 and Hoechst 33342 staining were employed and the expression levels of caspase-3 and -9 were assessed. Autophagy was examined by analysing the levels of LC3B-II and p62 and quantitating GFP-LC3B by fluorescence microscopy. A luciferase reporter assay investigated the putative binding sites of miR-30b. The effects of miR-30b and antimiR-30b on autophagy, apoptosis and osteogenic differentiation of TNF-α-treated cells were determined by autophagosome, apoptosis and alkaline phosphatase assays, respectively. Results: TNF-α exposure decreased cell viability, increased apoptosis and positively regulated autophagy in ADTC5 cells. A direct interaction was detected between miR-30b and the mRNA 3ʹ-UTRs of autophagy genes BECN1 and ATG5. Overexpression of miR-30b downregulated autophagy genes and upregulated pro-apoptotic gene expression in TNF-α-treated cells, while treatment with antimiR-30b had the inverse effect. Overexpression of miR-30b also downregulated ECM degradation and anti-miR-30b reverse TNF-α-induced ECM degradation. Conclusions: Anti-miR-30b enhanced autophagy and attenuated cartilage degradation and played a protective role in TNF-α-induced apoptosis of ATDC5 cells. Anti-miR-30b may therefore elevate cellular survival during inflammation and has therapeutic potential for inflammatory diseases such as osteoarthritis.

scholarly journals Antcin K Inhibits TNF-α, IL-1β and IL-8 Expression in Synovial Fibroblasts and Ameliorates Cartilage Degradation: Implications for the Treatment of Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
David Achudhan ◽  
Shan-Chi Liu ◽  
Yen-You Lin ◽  
Chien-Chung Huang ◽  
Chun-Hao Tsai ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cytokine Production ◽  
Bone Erosion ◽  
Interleukin 1 ◽  
Synovial Fibroblasts ◽  
Nuclear Factor Κb ◽  
Cartilage Degradation ◽  
Signaling Cascades ◽  
Necrosis Factor Alpha ◽  
Tnf Α

Extracts from Taiwan’s traditional medicinal mushroom, Antrodia cinnamomea, exhibit anti-inflammatory activities in cellular and preclinical studies. However, this paper is the first to report that Antcin K, a triterpenoid isolated from A. cinnamomea, inhibits proinflammatory cytokine production in human rheumatoid synovial fibroblasts (RASFs), which are major players in rheumatoid arthritis (RA) disease. In our analysis of the mechanism of action, Antcin K inhibited the expression of three cytokines (tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1β] and IL-8) in human RASFs; cytokines that are crucial to RA synovial inflammation. Notably, incubation of RASFs with Antcin K reduced the phosphorylation of the focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and nuclear factor-κB (NF-κB) signaling cascades, all of which promote cytokine production in RA. Intraperitoneal injections of Antcin K (10 mg/kg or 30 mg/kg) attenuated paw swelling, cartilage degradation and bone erosion, and decreased serum levels of TNF-α, IL-1β, IL-8 in collagen-induced arthritis (CIA) mice; in further experiments, IL-6 levels were similarly reduced. The inhibitory effects of Antcin K upon TNF-α, IL-1β and IL-8 expression in human RASFs was achieved through the downregulation of the FAK, PI3K, AKT and NF-κB signaling cascades. Our data support clinical investigations using Antcin K in RA disease.

scholarly journals Differences of plasma IL-1 and TNF-α in healthy Chinese Population

Open Medicine ◽  
2015 ◽  
Vol 10 (1) ◽  
Author(s):  
Jintao Yuan ◽  
Lan Wang ◽  
Yijin Lin ◽  
Jianhong Chen ◽  
Jianghong Hu
Keyword(s):  
Immune Responses ◽  
Opportunistic Infections ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Predictive Biomarkers ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tnf Α ◽  
Inflammatory Processes ◽  
Factor Α ◽  
Necrosis Factor

AbstractPle iotropic proinflammatory cytokines, interleukin- 1 (IL-1) and tumor necrosis factor-α (TNF-α), involved in the regulations of various immune responses, inflammatory processes and hematopoiesis. In the present study, the expression levels of IL-1 and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA). Following the cytokine blockade as a successful clinical therapy for autoimm une diseases such as rheumatoid arthritis, the patients are more susceptible to a variety of opportunistic infections. IL-1 and TNF-α may be useful predictive biomarkers of diseases and offer potential targets for therapeutic intervention of inflammatory diseases. However, our results showed that the plasma IL-1 level was significantly higher in women compared to men (69.5 ± 19.8 pg/ ml in men and 80.1 ± 19.5 pg/ml in women, respectively); the plasma levels of TNF-α were higher in men than women (20.8 ± 4.9 pg/ml and 18.7 ± 7.1 pg/ml, respectively). The significant gender difference of plasma interleukin-1 (IL-1) and TNF-α levels present in healthy adults in Jiangsu Province, China (P=0.002 and P=0.015, respectively), and may be as a hint for sex differences of susceptibility to many diseases and elementary immune response.

scholarly journals MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation

2007 ◽  
Vol 204 (7) ◽  
pp. 1637-1652 ◽  
Author(s):  
Magdalena M. Gorska ◽  
Qiaoling Liang ◽  
Susan J. Stafford ◽  
Nicolas Goplen ◽  
Nilesh Dharajiya ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Inflammatory Diseases ◽  
Endothelial Permeability ◽  
Mitogen Activated Protein Kinase ◽  
Activation Pattern ◽  
Nuclear Retention ◽  
Mitogen Activated Protein ◽  
Th2 Immunity ◽  
High Level ◽  
Transcriptional Output

We demonstrate that mitogen-activated protein kinase–activated kinase-2 (MK2) is essential for localized Th2-type inflammation and development of experimental asthma. MK2 deficiency does not affect systemic Th2 immunity, but reduces endothelial permeability, as well as adhesion molecule and chemokine expression. NF-κB regulates transcription of adhesion molecules and chemokines. We show that MK2 and its substrate HSP27 are essential for sustained NF-κB activation. MK2 and HSP27 prevent nuclear retention of p38 by sequestering it in the cytosol. As a result, MK2 precludes excessive phosphorylation of MSK1. By reducing MSK1 activity, MK2 prevents p65 NF-κB hyperphosphorylation and excessive IκBα transcription. IκBα mediates nuclear export of p65. By reducing IκBα level, MK2 prevents premature export of NF-κB from the nucleus. Thus, the MK2–HSP27 pathway regulates the NF-κB transcriptional output by switching the activation pattern from high level, but short lasting, to moderate-level, but long lasting. This pattern of activation is essential for many NF-κB–regulated genes and development of inflammation. Thus, the MK2–HSP27 pathway is an excellent target for therapeutic control of localized inflammatory diseases.

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