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Brain and Behavior Feb 2021The stress response is different in various individuals, however, the mechanisms that could explain these distinct effects are not well known and the molecular... (Review)
Review
INTRODUCTION
The stress response is different in various individuals, however, the mechanisms that could explain these distinct effects are not well known and the molecular correlates have been considered one at the time. Particular harmful conditions occur if the subject, instead to cope the stressful events, succumb to them, in this case, a cascade reaction happens that through different signaling causes a specific reaction named "sickness behaviour." The aim of this article is to review the complex relations among important molecules belonging to Central nervous system (CNS), immune system (IS), and endocrine system (ES) during the chronic stress response.
METHODS
After having verified the state of art concerning the function of cortisol, norepinephrine (NE), interleukin (IL)-1β and melatonin, we describe as they work together.
RESULTS
We propose a speculative hypothesis concerning the complex interplay of these signaling molecules during chronic stress, highlighting the role of IL-1β as main biomarker of this effects, indeed, during chronic stress its increment transforms this inflammatory signal into a nervous signal (NE), in turn, this uses the ES (melatonin and cortisol) to counterbalance again IL-1β. During cortisol resistance, a vicious loop occurs that increments all mediators, unbalancing IS, ES, and CNS networks. This IL-1β increase would occur above all when the individual succumbs to stressful events, showing the Sickness Behaviour Symptoms. IL-1β might, through melatonin and vice versa, determine sleep disorders too.
CONCLUSION
The molecular links here outlined could explain how stress plays a role in etiopathogenesis of several diseases through this complex interplay.
Topics: Circadian Rhythm; Endocrine System; Humans; Hydrocortisone; Immune System; Interleukin-1beta; Melatonin
PubMed: 33295155
DOI: 10.1002/brb3.1960 -
Frontiers in Immunology 2020Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a member of the MAPK kinase kinase (MAPKKK) family and has been implicated in the regulation of a... (Review)
Review
Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a member of the MAPK kinase kinase (MAPKKK) family and has been implicated in the regulation of a wide range of physiological and pathological processes. TAK1 functions through assembling with its binding partners TAK1-binding proteins (TAB1, TAB2, and TAB3) and can be activated by a variety of stimuli such as tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and toll-like receptor ligands, and they play essential roles in the activation of NF-κB and MAPKs. Numerous studies have demonstrated that post-translational modifications play important roles in properly controlling the activity, stability, and assembly of TAK1-TABs complex according to the indicated cellular environment. This review focuses on the recent advances in TAK1-TABs-mediated signaling and the regulations of TAK1-TABs complex by post-translational modifications.
Topics: Adaptor Proteins, Signal Transducing; Animals; Humans; Inflammation; Interleukin-1beta; MAP Kinase Kinase Kinases; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 33469458
DOI: 10.3389/fimmu.2020.608976 -
Molecular Cell Jun 2023Interleukin-1β (IL-1β) is a key protein in inflammation and contributes to tumor progression. However, the role of IL-1β in cancer is ambiguous or even contradictory....
Interleukin-1β (IL-1β) is a key protein in inflammation and contributes to tumor progression. However, the role of IL-1β in cancer is ambiguous or even contradictory. Here, we found that upon IL-1β stimulation, nicotinamide nucleotide transhydrogenase (NNT) in cancer cells is acetylated at lysine (K) 1042 (NNT K1042ac) and thereby induces the mitochondrial translocation of p300/CBP-associated factor (PCAF). This acetylation enhances NNT activity by increasing the binding affinity of NNT for NADP and therefore boosts NADPH production, which subsequently sustains sufficient iron-sulfur cluster maintenance and protects tumor cells from ferroptosis. Abrogating NNT K1042ac dramatically attenuates IL-1β-promoted tumor immune evasion and synergizes with PD-1 blockade. In addition, NNT K1042ac is associated with IL-1β expression and the prognosis of human gastric cancer. Our findings demonstrate a mechanism of IL-1β-promoted tumor immune evasion, implicating the therapeutic potential of disrupting the link between IL-1β and tumor cells by inhibiting NNT acetylation.
Topics: Humans; NADP Transhydrogenases; Interleukin-1beta; Acetylation; Protein Processing, Post-Translational; Immunotherapy; Neoplasms
PubMed: 37244254
DOI: 10.1016/j.molcel.2023.05.011 -
The Journal of Allergy and Clinical... Nov 2020Autoinflammatory diseases are conditions in which pathogenic inflammation arises primarily through antigen-independent hyperactivation of immune pathways. First... (Review)
Review
Autoinflammatory diseases are conditions in which pathogenic inflammation arises primarily through antigen-independent hyperactivation of immune pathways. First recognized just over 2 decades ago, the autoinflammatory disease spectrum has expanded rapidly to include more than 40 distinct monogenic conditions. Related mechanisms contribute to common conditions such as gout and cardiovascular disease. Here, we review the basic concepts underlying the "autoinflammatory revolution" in the understanding of immune-mediated disease and introduce major categories of monogenic autoinflammatory disorders recognized to date, including inflammasomopathies and other IL-1-related conditions, interferonopathies, and disorders of nuclear factor kappa B and/or aberrant TNF activity. We highlight phenotypic presentation as a reflection of pathogenesis and outline a practical approach to the evaluation of patients with suspected autoinflammation.
Topics: Animals; Autoimmune Diseases; Humans; Immunity, Innate; Inflammasomes; Inflammation; Interferons; Interleukin-1; NF-kappa B; Phenotype; Tumor Necrosis Factor-alpha
PubMed: 33160483
DOI: 10.1016/j.jaci.2020.08.017 -
International Journal of Molecular... Oct 2022Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder with an unknown cause characterized by high-spiking fever, lymphadenopathy, hepatosplenomegaly,... (Review)
Review
Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder with an unknown cause characterized by high-spiking fever, lymphadenopathy, hepatosplenomegaly, hyperferritinemia, and leukocytosis. The clinical course can be divided into three significant patterns, each with a different prognosis: Self-limited or monophasic, intermittent or polycyclic systemic, and chronic articular. Two criteria sets have been validated. The Yamaguchi criteria are the most generally used, although the Fautrel criteria offer the benefit of adding ferritin and glycosylated ferritin values. AOSD's pathogenesis is not yet completely understood. Chemokines and pro-inflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6, IL-8, and IL-18, play a crucial role in the progression of illness, resulting in the development of innovative targeted therapeutics. There are no treatment guidelines for AOSD due to its rarity, absence of controlled research, and lack of a standard definition for remission and therapy objectives. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids (CS), and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are used in AOSD treatment. Biological therapy, including IL-1, IL-6, IL-18, and IL-17 inhibitors, as well as TNFα or Janus-kinases (JAKs) inhibitors, is administered to patients who do not react to CS and csDMARDs or achieve an inadequate response.
Topics: Adult; Humans; Still's Disease, Adult-Onset; Interleukin-18; Tumor Necrosis Factor-alpha; Interleukin-6; Antirheumatic Agents; Adrenal Cortex Hormones; Interleukin-1
PubMed: 36361602
DOI: 10.3390/ijms232112810 -
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 -
Cancer Cell Jan 2024Cells in the tumor microenvironment (TME) influence each other through secretion and sensing of soluble mediators, such as cytokines and chemokines. While signaling of...
Cells in the tumor microenvironment (TME) influence each other through secretion and sensing of soluble mediators, such as cytokines and chemokines. While signaling of interferon γ (IFNγ) and tumor necrosis factor α (TNFα) is integral to anti-tumor immune responses, our understanding of the spatiotemporal behavior of these cytokines is limited. Here, we describe a single cell transcriptome-based approach to infer which signal(s) an individual cell has received. We demonstrate that, contrary to expectations, CD8 T cell-derived IFNγ is the dominant modifier of the TME relative to TNFα. Furthermore, we demonstrate that cell pools that show abundant IFNγ sensing are characterized by decreased expression of transforming growth factor β (TGFβ)-induced genes, consistent with IFNγ-mediated TME remodeling. Collectively, these data provide evidence that CD8 T cell-secreted cytokines should be categorized into local and global tissue modifiers, and describe a broadly applicable approach to dissect cytokine and chemokine modulation of the TME.
Topics: Humans; Cytokines; Tumor Necrosis Factor-alpha; Tumor Microenvironment; Interferon-gamma; CD8-Positive T-Lymphocytes
PubMed: 38194914
DOI: 10.1016/j.ccell.2023.12.010 -
ACS Nano Apr 2023Integrins expressed on extracellular vesicles (EVs) secreted by various cancers are reported to mediate the organotropism of these EVs. Our previous experiment found...
Integrins expressed on extracellular vesicles (EVs) secreted by various cancers are reported to mediate the organotropism of these EVs. Our previous experiment found that pancreatic tissue of mice with severe cases of acute pancreatitis (SAP) overexpresses several integrins and that serum EVs of these mice (SAP-EVs) can mediate acute lung injury (ALI). It is unclear if SAP-EV express integrins that can promote their accumulation in the lung to promote ALI. Here, we report that SAP-EV overexpress several integrins and that preincubation of SAP-EV with the integrin antagonist peptide HYD-1 markedly attenuates their pulmonary inflammation and disrupt the pulmonary microvascular endothelial cell (PMVEC) barrier. Further, we report that injecting SAP mice with EVs engineered to overexpress two of these integrins (ITGAM and ITGB2) can attenuate the pulmonary accumulation of pancreas-derived EVs and similarly decrease pulmonary inflammation and disruption of the endothelial cell barrier. Based on these findings, we propose that pancreatic EVs can mediate ALI in SAP patients and that this injury response could be attenuated by administering EVs that overexpress ITGAM and/or ITGB2, which is worthy of further study due to the lack of effective therapies for SAP-induced ALI.
Topics: Mice; Animals; Pancreatitis; Acute Disease; Tumor Necrosis Factor-alpha; Acute Lung Injury; Lung; Integrins
PubMed: 37022097
DOI: 10.1021/acsnano.2c12722 -
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 -
Brain, Behavior, and Immunity Jul 2020The magnitude and variability of cytokine alterations in depression are not clear. (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
The magnitude and variability of cytokine alterations in depression are not clear.
OBJECTIVE
To perform an up to date meta-analysis of mean differences of immune markers in depression, and to quantify and test for evidence of heterogeneity in immune markers in depression by conducting a meta-analysis of variability to ascertain whether only a sub-group of patients with depression show evidence of inflammation.
DATA SOURCES
Studies that reported immune marker levels in peripheral blood in patients with depression and matched healthy controls in the MEDLINE database from inception to August 29th 2018 were examined.
STUDY SELECTION
Case-control studies that reported immune marker levels in peripheral blood in patients with depression and healthy controls were selected.
DATA EXTRACTION AND SYNTHESIS
Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis.
MAIN OUTCOMES AND MEASURES
Hedges g was used to quantify mean differences. Relative variability of immune marker measurements in patients compared with control groups as indexed by the coefficient of variation ratio (CVR).
RESULTS
A total of 107 studies that reported measurements from 5,166 patients with depression and 5,083 controls were included in the analyses. Levels of CRP (g = 0.71; 95%CI: 0.50-0.92; p < 0.0001); IL-3 (g = 0.60; 95%CI: 0.31-0.89; p < 0.0001); IL-6 (g = 0.61; 95%CI: 0.39-0.82; p < 0.0001); IL-12 (g = 1.18; 95%CI: 0.74-1.62; p < 0.0001); IL-18 (g = 1.97; 95%CI: 1.00-2.95; p < 0.0001); sIL-2R (g = 0.71; 95%CI: 0.44-0.98; p < 0.0001); and TNFα (g = 0.54; 95%CI: 0.32-0.76; p < 0.0001) were significantly higher in patients with depression. These findings were robust to a range of potential confounds and moderators. Mean-scaled variability, measured as CVR, was significantly lower in patients with depression for CRP (CVR = 0.85; 95%CI: 0.75-0.98; p = 0.02); IL-12 (CVR = 0.61; 95%CI: 0.46-0.80; p < 0.01); and sIL-2R (CVR = 0.85; 95%CI: 0.73-0.99; p = 0.04), while it was unchanged for IL-3, IL-6, IL-18, and TNF α.
CONCLUSIONS AND RELEVANCE
Depression is confirmed as a pro-inflammatory state. Some of the inflammatory markers elevated in depression, including CRP and IL-12, show reduced variability in patients with depression, therefore supporting greater homogeneity in terms of an inflammatory phenotype in depression. Some inflammatory marker elevations in depression do not appear due to an inflamed sub-group, but rather to a right shift of the immune marker distribution.
Topics: Biomarkers; Cytokines; Depression; Humans; Inflammation; Tumor Necrosis Factor-alpha
PubMed: 32113908
DOI: 10.1016/j.bbi.2020.02.010