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Nature Reviews. Rheumatology Jan 2016TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce... (Review)
Review
TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce new concepts for the development of therapeutics for TNF-mediated diseases. The model of TNF receptor signalling has been extended to include linear ubiquitination and the formation of distinct signalling complexes that are linked with different functional outcomes, such as inflammation, apoptosis and necroptosis. Our understanding of TNF-induced gene expression has been enriched by the discovery of epigenetic mechanisms and concepts related to cellular priming, tolerization and induction of 'short-term transcriptional memory'. Identification of distinct homeostatic or pathogenic TNF-induced signalling pathways has introduced the concept of selectively inhibiting the deleterious effects of TNF while preserving its homeostatic bioactivities for therapeutic purposes. In this Review, we present molecular mechanisms underlying the roles of TNF in homeostasis and inflammatory disease pathogenesis, and discuss novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases.
Topics: Gene Expression Regulation; Genetic Therapy; Humans; Inflammation; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 26656660
DOI: 10.1038/nrrheum.2015.169 -
Experimental Gerontology Oct 2022Sarcopenia is a progressive skeletal muscle disease that occurs most commonly in the elderly population, contributing to increased costs and hospitalization. Exercise... (Review)
Review
Sarcopenia is a progressive skeletal muscle disease that occurs most commonly in the elderly population, contributing to increased costs and hospitalization. Exercise and nutritional therapy have been proven to be effective for sarcopenia, and some drugs can also alleviate declines in muscle mass and function due to sarcopenia. However, there is no specific pharmacological treatment for sarcopenia at present. This review will mainly discuss the relationship between inflammaging and sarcopenia. The increased secretion of proinflammatory cytokines with aging may be because of cellular senescence, immunosenescence, alterations in adipose tissue, damage-associated molecular patterns (DAMPs), and gut microbes due to aging. These sources of inflammaging can impact the sarcopenia process through direct or indirect pathways. Conversely, sarcopenia can also aggravate the process of inflammaging, creating a vicious cycle. Targeting sources of inflammaging can influence muscle function, which could be considered a therapeutic target for sarcopenia. Moreover, not only proinflammatory cytokines but also anti-inflammatory cytokines can influence muscle and inflammation and participate in the progression of sarcopenia. This review focuses on the effects of TNF-α, IL-6, and IL-10, which can be detected in plasma. Therefore, clearing chronic inflammation by targeting proinflammatory cytokines (TNF-α, IL-1, IL-6) and the inflammatory pathway (JAK/STAT, autophagy, NF-κB) may be effective in treating sarcopenia.
Topics: Aged; Aging; Anti-Inflammatory Agents; Cytokines; Humans; Inflammation; Interleukin-1; Interleukin-10; Interleukin-6; NF-kappa B; Sarcopenia; Tumor Necrosis Factor-alpha
PubMed: 35985553
DOI: 10.1016/j.exger.2022.111931 -
Advances in Experimental Medicine and... 2016The interleukin-1 (IL-1) family consists of several pro- or anti-inflammatory proteins, with pro-inflammatory IL-1β being its best characterized member. IL-1β is one... (Review)
Review
The interleukin-1 (IL-1) family consists of several pro- or anti-inflammatory proteins, with pro-inflammatory IL-1β being its best characterized member. IL-1β is one of the most prominent mediators of inflammation resulting in fever and immune activation via binding to IL-1 receptor 1. Due to its potency, its secretion is tightly regulated. First the transcription of the biologically inactive proform is induced by TLR activation, TNF, or IL-1 receptor activation by mature IL-1α or IL-1β. For the secretion of IL-1β, inflammasome activation as second stimulus is needed. Inflammasomes are cytosolic protein complexes whose activation results in the maturation of inflammatory caspases such as caspase-1. Caspase-1 then cleaves the inactive pro-IL-1β into its mature form which is then being secreted. While IL-1α and IL-1β are considered pro-inflammatory, IL-1Ra as a naturally occurring receptor antagonist acts as an inhibitor on IL-1 receptor signaling. Further members of the IL-1 family, such as IL-18, IL-33, or IL-36, are even involved in T-helper-cell differentiation and will also be discussed in this chapter.
Topics: Animals; Humans; Inflammasomes; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-1alpha; Interleukin-1beta; Multigene Family; Protein Isoforms; Signal Transduction
PubMed: 27734407
DOI: 10.1007/978-94-024-0921-5_2 -
Biomedicine & Pharmacotherapy =... Nov 2020Low back pain (LBP), a prevalent and costly disease around the world, is predominantly caused by intervertebral disc (IVD) degeneration (IDD). LBP also presents a... (Review)
Review
Low back pain (LBP), a prevalent and costly disease around the world, is predominantly caused by intervertebral disc (IVD) degeneration (IDD). LBP also presents a substantial burden to public health and the economy. IDD is mainly caused by aging, trauma, genetic susceptibility, and other factors. It is closely associated with changes in tissue structure and function, including progressive destruction of the extracellular matrix (ECM), enhanced senescence, disc cell death, and impairment of tissue biomechanical function. The inflammatory process, exacerbated by cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), are considered to be the key mediators of IDD and LBP. IL-1β and TNF-α are the most important proinflammatory cytokines, as they have powerful proinflammatory activities and can promote the secretion of a variety of proinflammatory mediators. They are also upregulated in the degenerative IVDs, and they are closely related to various pathological IDD processes, including inflammatory response, matrix destruction, cellular senescence, autophagy, apoptosis, pyroptosis, and proliferation. Therefore, anti-IL-1β and anti-TNF-α therapies may have the potential to alleviate disc degeneration and LBP. In this paper, we reviewed the expression pattern and signal transduction pathways of IL-1β and TNF-α, and we primarily focused on their similar and different roles in IDD. Because IL-1β and TNF-α inhibition have the potential to alleviate IDD, an in-depth understanding of the role of IL-1β and TNF-α in IDD will benefit the development of new treatment methods for disc degeneration with IL-1β and TNF-α at the core.
Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Humans; Interleukin-1beta; Intervertebral Disc Degeneration; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 32853910
DOI: 10.1016/j.biopha.2020.110660 -
Journal of Cellular Biochemistry Jan 2018Pathogenesis of type 2 diabetes mellitus (T2DM) and development of insulin resistance are characterized by multi-stimuli factors notably glucolipotoxicity, generation of... (Review)
Review
Pathogenesis of type 2 diabetes mellitus (T2DM) and development of insulin resistance are characterized by multi-stimuli factors notably glucolipotoxicity, generation of reactive oxygen species (ROS), epigenetic factors, activation of various transcriptional mediated pathways along with the augmented levels of various pro-inflammatory cytokines. Among the various pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) is one the most important pro-inflammatory mediator that is critically involved in the development of insulin resistance and pathogenesis of T2DM. TNF-α is mainly produced in adipocytes and/or peripheral tissues, and induces tissue-specific inflammation through the involvement of generation of ROS and activation of various transcriptional mediated pathways. The raised level of TNF-α induces insulin resistance in adipocytes and peripheral tissues by impairing the insulin signaling through serine phosphorylation that leads to the development of T2DM. Anti-TNF-α treatment strategies have been developed to reduce the incidence of insulin resistance and development of T2DM. In this article, we have briefly described how TNF-α plays crucial role to induce insulin resistance and pathogenesis of T2DM. To block the inflammatory responses by blocking TNF-α and TNF-α signaling may be an effective strategy for the treatment of insulin resistance and T2DM. J. Cell. Biochem. 119: 105-110, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Tumor Necrosis Factor-alpha
PubMed: 28569437
DOI: 10.1002/jcb.26174 -
Cell Stem Cell Jan 2022In aging, androgenic alopecia, and genetic hypotrichosis disorders, hair shaft miniaturization is often associated with hair follicle stem cell (HFSC) loss. However, the...
In aging, androgenic alopecia, and genetic hypotrichosis disorders, hair shaft miniaturization is often associated with hair follicle stem cell (HFSC) loss. However, the mechanism causing this stem cell depletion in vivo remains elusive. Here we show that hair shaft loss or a reduction in diameter shrinks the physical niche size, which results in mechanical compression of HFSCs and their apoptotic loss. Mechanistically, cell compression activates the mechanosensitive channel Piezo1, which triggers calcium influx. This confers tumor necrosis factor alpha (TNF-α) sensitivity in a hair-cycle-dependent manner in otherwise resistant HFSCs and induces ectopic apoptosis. Persistent hair shaft miniaturization during aging and genetic hypotrichosis disorders causes long-term HFSC loss by inducing continuous ectopic apoptosis through Piezo1. Our results identify an unconventional role of the inert hair shaft structure as a functional niche component governing HFSC survival and reveal a mechanosensory axis that regulates physical-niche-atrophy-induced stem cell depletion in vivo.
Topics: Calcium; Hair Follicle; Miniaturization; Stem Cells; Tumor Necrosis Factor-alpha
PubMed: 34624205
DOI: 10.1016/j.stem.2021.09.009 -
Annals of the Rheumatic Diseases Apr 2023Syntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal...
OBJECTIVES
Syntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA.
METHODS
RA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape.
RESULTS
Syntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (MΦs) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14CD86GLUT1MΦs reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA MΦs-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80iNOSRAPTORMΦs represent glycolytic RA MΦs, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1 animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated MΦ remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation.
CONCLUSION
The syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic MΦ and Th1 cell cross-regulation (graphical abstract).
Topics: Animals; Humans; Arthritis, Rheumatoid; Endothelial Cells; Macrophages; Monokines; Syndecan-1; Synovial Fluid; Synovial Membrane; Syntenins; Th1 Cells; TOR Serine-Threonine Kinases
PubMed: 36593091
DOI: 10.1136/ard-2022-223284 -
Cardiovascular Diabetology Jan 2024Type 1 diabetes (T1D) is a significant risk factor for a range of cardiovascular diseases. Nonetheless, the causal relationship between T1D and non-ischemic...
BACKGROUND
Type 1 diabetes (T1D) is a significant risk factor for a range of cardiovascular diseases. Nonetheless, the causal relationship between T1D and non-ischemic cardiomyopathy (NICM) remains to be elucidated. Furthermore, the mechanisms responsible for the progression from T1D to NICM have not been definitively characterized.
OBJECTIVE
The aim of this study was to conduct a Mendelian randomization (MR) study to investigate the causal effects of T1D and its complications on the development of NICM. Additionally, this study aimed to conduct a mediation analysis to identify potential mediators within this correlation.
METHODS
Genetic variants were used as instrumental variables for T1D. The summary data for T1D were obtained from two genome-wide association study datasets. The summary data for T1D with complications and NICM were obtained from the Finnish database. Two-sample MR, multivariable MR and mediation MR were conducted in this study.
RESULTS
The study revealed a causal association between T1D, T1D with complications, and NICM (with odds ratios of 1.02, 95% CI 1.01-1.04, p = 1.17e-04 and 1.03, 95% CI 1.01-1.05, p = 3.15e-3). Even after adjusting for confounding factors such as body mass index and hypertension, T1D remained statistically significant (with odds ratio of 1.02, 95% CI 1.01-1.04, p = 1.35e-4). Mediation analysis indicated that monokine induced by gamma interferon may play a mediating role in the pathogenesis of T1D-NICM (mediation effect indicated by odds ratio of 1.005, 95% CI 1.001-1.01, p = 4.9e-2).
CONCLUSION
The study demonstrates a causal relationship between T1D, its complications, and NICM. Additionally, monokine induced by gamma interferon may act as a potential mediator in the pathogenesis of T1D-NICM.
Topics: Humans; Diabetes Mellitus, Type 1; Genome-Wide Association Study; Interferon-gamma; Mendelian Randomization Analysis; Myocardial Ischemia; Monokines; Cardiomyopathies; Polymorphism, Single Nucleotide
PubMed: 38218861
DOI: 10.1186/s12933-023-02117-7 -
Hepatology (Baltimore, Md.) Aug 2020The proinflammatory cytokine IL-1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL-1β promotes liver injury in these...
BACKGROUND AND AIMS
The proinflammatory cytokine IL-1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL-1β promotes liver injury in these diseases is unclear, as no IL-1β receptor-linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy's function in hepatotoxicity from proinflammatory cytokines.
APPROACH AND RESULTS
AML12 cells with decreased autophagy from a lentiviral autophagy-related 5 (Atg5) knockdown were resistant to toxicity from TNF, but sensitized to death from IL-1β, which was markedly amplified by TNF co-treatment. IL-1β/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin-1s to prevent death. IL-1β/TNF depleted autophagy-deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL-1β/TNF-induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy-deficient cells. Mice with a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were similarly sensitized to cathepsin-dependent hepatocellular injury and death from IL-1β/TNF in combination, but neither IL-1β nor TNF alone. Knockout mice had increased hepatic inflammation, and IL-1β/TNF-treated, autophagy-deficient AML12 cells secreted exosomes with proinflammatory damage-associated molecular patterns.
CONCLUSIONS
The findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL-1β/TNF-induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage-associated molecular patterns.
Topics: Animals; Autophagy; Cells, Cultured; Female; Hepatocytes; Inflammation; Interleukin-1beta; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Tumor Necrosis Factor-alpha
PubMed: 32108953
DOI: 10.1002/hep.31209 -
Inflammatory Bowel Diseases May 2023Janus kinase (JAK) 1 inhibitor upadacitinib and IL-23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are antitumor necrosis...
BACKGROUND
Janus kinase (JAK) 1 inhibitor upadacitinib and IL-23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are antitumor necrosis factor (anti-TNF)-α inadequate responders (TNF-IRs). We aimed to understand the mechanisms mediating the response of upadacitinib and risankizumab.
METHODS
Eight tissue transcriptomic data sets from IBD patients treated with anti-TNF-α therapies along with single-cell RNAseq data from ulcerative colitis were integrated to identify TNF-IR mechanisms. The RNAseq colon tissue data from clinical studies of TNF-IR Crohn's disease patients treated with upadacitinib or risankizumab were used to identify TNF-IR mechanisms that were favorably modified by upadacitinib and risankizumab.
RESULTS
We found 7 TNF-IR upregulated modules related to innate/adaptive immune responses, interferon signaling, and tissue remodeling and 6 TNF-IR upregulated cell types related to inflammatory fibroblasts, postcapillary venules, inflammatory monocytes, macrophages, dendritic cells, and cycling B cells. Upadacitinib was associated with a significant decrease in the expression of most TNF-IR upregulated modules in JAK1 responders (JAK1-R); in contrast, there was no change in these modules among TNF-IR patients treated with a placebo or among JAK1 inadequate responders (JAK1-IR). In addition, 4 of the 6 TNF-IR upregulated cell types were significantly decreased after upadacitinib treatment in JAK1-R but not among subjects treated with a placebo or among JAK1-IR patients. We observed similar findings from colon biopsy samples from TNF-IR patients treated with risankizumab.
CONCLUSIONS
Collectively, these data suggest that upadacitinib and risankizumab affect TNF-IR upregulated mechanisms, which may account for their clinical response among TNF-IR IBD patients.
Topics: Humans; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Inflammatory Bowel Diseases
PubMed: 36515243
DOI: 10.1093/ibd/izac246