scholarly journals cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing Tregs

2019 ◽  
Vol 5 (5) ◽  
pp. eaaw5422 ◽  
Author(s):  
Joanna Z. Kawalkowska ◽  
Joy Ogbechi ◽  
Patrick J. Venables ◽  
Richard O. Williams
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Treatment Withdrawal ◽  
Collagen Induced Arthritis ◽  
Inhibitors Of Apoptosis ◽  
Tnf Α ◽  
Cellular Inhibitors ◽  
Effector Cytokines ◽  
Tnf Inhibition

IL-17 and TNF-α are major effector cytokines in chronic inflammation. TNF-α inhibitors have revolutionized the treatment of rheumatoid arthritis (RA), although not all patients respond, and most relapse after treatment withdrawal. This may be due to a paradoxical exacerbation of TH17 responses by TNF-α inhibition. We examined the therapeutic potential of targeting cellular inhibitors of apoptosis 1 and 2 (cIAP1/2) in inflammation by its influence on human TH subsets and mice with collagen-induced arthritis. Inhibition of cIAP1/2 abrogated CD4+ IL-17A differentiation and IL-17 production. This was a direct effect on T cells, mediated by reducing NFATc1 expression. In mice, cIAP1/2 inhibition, when combined with etanercept, abrogated disease activity, which was associated with an increase in Tregs and was sustained after therapy retraction. We reveal an unexpected role for cIAP1/2 in regulating the balance between TH17 and Tregs and suggest that combined therapeutic inhibition could induce long-term remission in inflammatory diseases.

scholarly journals Skullcapflavone II Suppresses TNF-α/IFN-γ-Induced TARC, MDC, and CTSS Production in HaCaT Cells

2021 ◽  
Vol 22 (12) ◽  
pp. 6428
Author(s):  
Hanon Lee ◽  
Dong Hun Lee ◽  
Jang-Hee Oh ◽  
Jin Ho Chung
Keyword(s):  
P38 Mapk ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Mapk Signaling ◽  
Hacat Cells ◽  
Protein Levels ◽  
Tnf Α ◽  
Ifn Γ ◽  
Mapk Signaling Pathways ◽  
Pro Inflammatory Cytokines

Skullcapflavone II (SFII), a flavonoid derived from Scutellaria baicalensis, has been reported to have anti-inflammatory properties. However, its therapeutic potential for skin inflammatory diseases and its mechanism are unknown. Therefore, this study aimed to investigate the effect of SFII on TNF-α/IFN-γ-induced atopic dermatitis (AD)-associated cytokines, such as thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC). Co-stimulation with TNF-α/IFN-γ in HaCaT cells is a well-established model for induction of pro-inflammatory cytokines. We treated cells with SFII prior to TNF-α/IFN-γ-stimulation and confirmed that it significantly inhibited TARC and MDC expression at the mRNA and protein levels. Additionally, SFII also inhibited the expression of cathepsin S (CTSS), which is associated with itching in patients with AD. Using specific inhibitors, we demonstrated that STAT1, NF-κB, and p38 MAPK mediate TNF-α/IFN-γ-induced TARC and MDC, as well as CTSS expression. Finally, we confirmed that SFII significantly suppressed TNF-α/IFN-γ-induced phosphorylation of STAT1, NF-κB, and p38 MAPK. Taken together, our study indicates that SFII inhibits TNF-α/IFN-γ-induced TARC, MDC, and CTSS expression by regulating STAT1, NF-κB, and p38 MAPK signaling pathways.

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 Fibrinogen-Like Protein 1 Serves as an Anti-Inflammatory Agent for Collagen-Induced Arthritis Therapy in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Wen-Wei Lin ◽  
Kai-Wen Ho ◽  
Hsiang-Han Su ◽  
Tien-Fang Fang ◽  
Shey-Cherng Tzou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Intraperitoneal Administration ◽  
Collagen Induced Arthritis ◽  
Activated T Cells ◽  
Primary Mouse

Fibrinogen-like protein 1 (FGL1) was recently identified as a major ligand of lymphocyte-activation gene-3 (LAG-3) on activated T cells and serves as an immune suppressive molecule for regulation of immune homeostasis. However, whether FGL1 has therapeutic potential for use in the T cell-induced the autoimmune disease, rheumatoid arthritis (RA), is still unknown. Here, we attempted to evaluate the effect of FGL1 protein on arthritis progression. We also evaluated potential adverse events in a collagen-induced arthritis (CIA) mouse model. We first confirmed that soluble Fgl1 protein could specifically bind to surface Lag-3 receptor on 3T3-Lag-3 cells and further inhibit interleukin (IL-2) and interferon gamma (IFNγ) secretion from activated primary mouse T cells by 95% and 43%, respectively. Intraperitoneal administration of Fgl1 protein significantly decreased the inflammatory cytokine level (i.e., IL-1β and IL-6) in local paw tissue, and prevented joint inflammation, cellular infiltration, bone deformation and attenuated collagen-induced arthritis progression in vivo. We further demonstrated that exogenous Fgl1 does not cause obvious adverse events during treatment by monitoring body weight and liver weight, and assessing the morphology of several organs (i.e., heart, liver, spleen, lung and kidney) by pathological studies. We expect that Fgl1 protein may be suitable to serve as a potential therapeutic agent for treatment of RA or even other types of T cell-induced autoimmune or inflammatory diseases in the future.

scholarly journals Sulfasalazine Microparticles Targeting Macrophages for the Treatment of Inflammatory Diseases Affecting the Synovial Cavity

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 951
Author(s):  
Monica-Carolina Villa-Hermosilla ◽  
Ana Fernández-Carballido ◽  
Carolina Hurtado ◽  
Emilia Barcia ◽  
Consuelo Montejo ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Term Treatment ◽  
Particle Sizes ◽  
Duration Of Action ◽  
Tnf Α ◽  
Long Term Treatment ◽  
Inflammatory Processes

Rheumatoid arthritis (RA) is a chronic inflammatory disease with sulfasalazine (SSZ) extensively used for long-term treatment of both juvenile and adult RA. Its use is associated with adverse effects and toxicity due to its non-selective biodistribution. Macrophages play an important role in inflammatory processes. In order to target SSZ to macrophages in this work two microparticulate systems (MPs) are developed: SSZ-loaded PLGA MPs without and with α-tocopherol, with particle sizes lower than 5 μm and encapsulation efficiencies of 81.07 ± 11% and 63.50 ± 6.62%, respectively. Release of SSZ from MPs prepared with α-tocopherol was prolonged for 20 days. In RAW 264.7 cell macrophages MPs prepared with α-tocopherol were captured faster. Cell viability studies confirmed that SSZ-loaded MPs prepared without and with α-tocopherol did not produce cytotoxicity at the concentrations assayed. The anti-inflammatory activity of SSZ-loaded MPs was studied by quantifying interleukins IL-1, IL-6 and TNF-α in macrophages. All formulations produced a significant reduction of cytokine concentrations after 24 and 72 h, indicating that release of SSZ from the MPs was able to inhibit the inflammatory response induced by lipopolysaccharide (LPS). Gene expression of IL-1, IL-6 and TNF-α was decreased by SSZ-loaded MPs. SSZ-loaded MPs prepared with α-tocopherol will potentially allow increasing the residence time of SSZ in the synovial cavity, prolonging its duration of action, and reducing the adverse effects associated with its non-selective biodistribution.

scholarly journals Chemokine Receptor 5 Antagonism Causes Reduction in Joint Inflammation in a Collagen-Induced Arthritis Mouse Model

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1839
Author(s):  
Mushtaq A. Ansari ◽  
Ahmed Nadeem ◽  
Saleh A. Bakheet ◽  
Sabry M. Attia ◽  
Mudassar Shahid ◽  
...  
Keyword(s):  
T Cells ◽  
Chemokine Receptor ◽  
Cd8 T Cells ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Chronic Inflammatory Disease ◽  
Collagen Induced Arthritis ◽  
Protein Levels ◽  
Tnf Α ◽  
Chemokine Receptor 5

Rheumatoid arthritis (RA) is a chronic inflammatory disease mainly affecting the synovial joints. A highly potent antagonist of C-C chemokine receptor 5 (CCR5), maraviroc (MVC), plays an essential role in treating several infectious diseases but has not yet been evaluated for its potential effects on RA development. This study focused on evaluating the therapeutic potential of MVC on collagen-induced arthritis (CIA) in DBA/1J mice. Following CIA induction, animals were treated intraperitoneally with MVC (50 mg/kg) daily from day 21 until day 35 and evaluated for clinical score and histopathological changes in arthritic inflammation. We further investigated the effect of MVC on Th9 (IL-9, IRF-4, and GATA3) and Th17 (IL-21R, IL-17A, and RORγT) cells, TNF-α, and RANTES in CD8+ T cells in the spleen using flow cytometry. We also assessed the effect of MVC on mRNA and protein levels of IL-9, IL-17A, RORγT, and GATA3 in knee tissues using RT-PCR and western blot analysis. MVC treatment in CIA mice attenuated the clinical and histological severity of inflammatory arthritis, and it substantially decreased IL-9, IRF4, IL-21R, IL-17A, RORγT, TNF-α, and RANTES production but increased GATA3 production in CD8+ T cells. We further observed that MVC treatment decreased IL-9, IL-17A, and RORγt mRNA and protein levels and increased those of GATA3. This study elucidates the capacity of MVC to ameliorate the clinical and histological signs of CIA by reducing pro-inflammatory responses, suggesting that MVC may have novel therapeutic uses in the treatment of RA.

scholarly journals Bovine κ-Casein Fragment Induces Hypo-Responsive M2-Like Macrophage Phenotype

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1688 ◽  
Author(s):  
Richard Lalor ◽  
Sandra O’Neill
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Signal Transduction Pathway ◽  
Sodium Caseinate ◽  
Nuclear Factor Κb ◽  
Proteolytic Processing ◽  
Therapeutic Effects ◽  
Macrophage Phenotype ◽  
Inflammatory Conditions ◽  
Tnf Α

Immunomodulatory nutraceuticals have garnered special attention due to their therapeutic potential for the amelioration of many chronic inflammatory conditions. Macrophages are key players in the induction, propagation and resolution of inflammation, actively contributing to the pathogenesis and resolution of inflammatory disorders. As such, this study aimed to investigate the possible therapeutic effects bovine casein derived nutraceuticals exert on macrophage immunological function. Initial studies demonstrated that sodium caseinate induced a M2-like macrophage phenotype that was attributed to the kappa-casein subunit. Kappa-casein primed macrophages acquired a M2-like phenotype that expressed CD206, CD54, OX40L, CD40 on the cell surface and gene expression of Arg-1, RELM-α and YM1, archetypical M2 markers. Macrophages stimulated with kappa-casein secreted significantly reduced TNF-α and IL-10 in response to TLR stimulation through a mechanism that targeted the nuclear factor-κB signal transduction pathway. Macrophage proteolytic processing of kappa-casein was required to elicit these suppressive effects, indicating that a fragment other than C-terminal fragment, glycomacropeptide, induced these modulatory effects. Kappa-casein treated macrophages also impaired T-cell responses. Given the powerful immuno-modulatory effects exhibited by kappa-casein and our understanding of immunopathology associated with inflammatory diseases, this fragment has the potential as an oral nutraceutical and therefore warrants further investigation.

Therapeutic Potential of Adipose-Derived Stem Cells in the Treatment of Pulmonary Diseases

2021 ◽  
Vol 16 ◽  
Author(s):  
Nur Shuhaidatul Sarmiza Abdul Halim ◽  
Badrul Hisham Yahaya ◽  
Jie Lian
Keyword(s):  
Stem Cells ◽  
Distress Syndrome ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Trophic Factors ◽  
Chronic Obstructive ◽  
Adipose Derived Stem Cells ◽  
Obstructive Pulmonary Disease ◽  
Made In

: Stem cells derived from adipose tissues (ADSCs) have emerged as an ideal candidate for various models of respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome. ADSCs have qualities that may make them better suited for treating inflammatory lung diseases than other MSCs. ADSCs show a lower senescence ratio, higher proliferative capacity and stability in terms of their genetic and morphology during long-term culture over bone marrow-derived mesenchymal stem cells (BMMSCs). With advanced research techniques, the advantageous effects of ADSCs seem limited to their ability to engraft, differentiate, and be related to their secretion of trophic factors. These trophic factors regulate the therapeutic and regenerative outcomes in various lung inflammatory diseases. Taken together, these particular qualities of ADSCs make them significantly relevant for clinical applications. This article discusses a recent advance of ADSCs biology and their translational application emphasizing their anti-inflammatory, immunomodulatory and regenerative properties particularly on lung inflammatory diseases. Besides, the relevant advancements made in the field, the regulatory aspects, and other challenges and obstacles will be highlighted.

Inflammatory disease of the womans reproductive system: modern trends in diagnosis and therapy (literature review)

GYNECOLOGY ◽  
2018 ◽  
Vol 20 (6) ◽  
pp. 35-41
Author(s):  
T Yu Pestrikova ◽  
I V Yurasov ◽  
E A Yurasova
Keyword(s):  
Genital Tract ◽  
Inflammatory Diseases ◽  
Diagnosis And Treatment ◽  
Long Term Results ◽  
Modern Approach ◽  
Pelvic Organs ◽  
Results Of Treatment ◽  
Number Of Patients ◽  
Diagnostic Approaches

Medical, social and economic relevance of inflammatory diseases of the woman's reproductive organs requires a very careful attitude to the diagnosis and treatment of this pathology. The number of patients with genital infections and inflammatory diseases of the pelvic organs can takes the first place in structure of gynecological morbidity, and is 60.4-65.0%, and this fact is not unique to Russia, but all over the world. Incidence rate of inflammatory diseases of the pelvic organs in the first decade of the twenty-first century is increased at 1.4 times in patients who are from 18 to 24 years old and at 1.8 times in patients aged 25-29 years. At the same time, the cost of diagnosis and treatment has increased, reaching 50-60% of the total cost of providing gynecological care for population. The inflammatory diseases of pelvic organs are a collective concept. It includes of various nosological forms. There are numerous contradictions in the views on diagnostic approaches and treatment tactics, the nature of screening and control over the long-term results of treatment, the etiological and pathogenetic significance of various microorganisms found in the genital tract in patients with inflammatory diseases of the pelvic organs. Currently, there are many opinions among specialists about diagnostic approaches and treatment tactics, the type of screening and monitoring the long-term results of treatment, the etiological and pathogenetic role of various microorganisms which can be found in the genital tract in patients with inflammatory diseases. This review presents the results of a modern approach to the diagnosis, management and rehabilitation of patients with inflammatory diseases of the pelvic organs.

Sign in / Sign up

Export Citation Format

Share Document