scholarly journals Type 1 Interferons Suppress Accelerated Osteoclastogenesis and Prevent Loss of Bone Mass During Systemic Inflammatory Responses to Pneumocystis Lung Infection

2012 ◽  
Vol 181 (1) ◽  
pp. 151-162 ◽  
Author(s):  
Michelle Wilkison ◽  
Katherine Gauss ◽  
Yanchao Ran ◽  
Steve Searles ◽  
David Taylor ◽  
...  
Keyword(s):  
Bone Mass ◽  
Inflammatory Responses ◽  
Lung Infection ◽  
Type 1 Interferons

Glucocorticoids Differentially Target SOCS1 and Type 1 Interferons to Regulate TLR-Induced STAT-1 Activation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 239-239
Author(s):  
Sandip Bhattacharyya ◽  
Louis Muglia
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Janus Kinase ◽  
Poly I:C ◽  
Inflammatory Reactions ◽  
Wide Range ◽  
Pre Treatment ◽  
Novel Target ◽  
Type 1 Interferons

Abstract Abstract 239 Glucocorticoids (GCs) released endogenously or administered clinically limit the severity of a wide range of inflammatory and autoimmune diseases. Understanding GC action in modulating inflammatory reactions holds promise for the development of more efficacious therapy by minimizing the detrimental sequel of these drugs. In the context of inflammatory diseases, Toll-like receptors (TLRs) are well characterized to integrate and propagate inflammatory signals, while GCs inhibit inflammatory gene expression including cytokines. Several cytokines functions via the JAK-STAT (Janus Kinase-Signal Transducer and Activator of Transcription) pathway and promote transcription of STAT-responsive genes. Interestingly, almost all members of mammalian STAT super family, except STAT-1, are known to functionally synergize with GC. In the light of relatively less known GC-antagonizing nature of STAT-1, we explored STAT-1 regulation by GC in macrophages during activation of inflammatory pathways with TLR-specific ligands. We observed selective impairment of STAT-1 activation by GC, depending on the nature of TLR / TLR-adapter engagement. Most TLRs utilize the adapter MyD88 with the exception of TLR3, which exclusively recruits the adapter Trif. TLR4 is the only member that exploits both MyD88 and Trif to induce downstream targets of the signaling cascade. Secretion of proinflammatory cytokines e.g. TNF-α and IL-12 was 50 – 62 % inhibited in STAT-null macrophages during TLR4 (MyD88 / Trif) or TLR3 (Trif) engagement with LPS and Poly (I:C) respectively but not for TLR9 (MyD88) engagement with CpG. We also observed 2 – 15 fold suppression of STAT-1 phosphorylation (at Ser727 and Tyr701) by Dex (Dexamethasone, a chemical analogue of GC) in LPS or Poly (I:C) treated macrophages. There was little effect of Dex during CpG treatment. Pre-treatment with anti-IFN receptor 1 (IFNAR1) antibody indicated TLR3 or TLR4 induced STAT-1 phosphorylation is IFN-dependent. Unexpectedly, IFN-β dependent STAT-1 phosphorylation was found to be Dex-resistant indicating little or no role of GC on IFN-mediated STAT-1 activation. But, we observed 2.5 - 4 fold suppression by Dex for Poly (I:C) induced IFN-α, IFN-β secretion and 2 - 2.8 fold suppression of nuclear interferon regulatory factor 3 (IRF-3) level, but not for LPS. IRF-3 is known as a critical component for IFN induction. Our results indicate GC impairs Trif-mediated STAT-1 activity by inhibiting IFN production and not via direct inhibition of IFN function. CpG did not induce IFN-α, IFN-β secretion or STAT-1 phosphorylation at Tyr701. Furthermore, we found 2 – 5 fold elevation of suppressor of cytokine synthesis 1 (SOCS1) level by Dex in either case of TLR4 or TLR3 engagement. We hypothesize that GC attenuates MyD88–Trif-mediated STAT-1 activation via induction of SOCS1. Intriguingly, inhibition of Trif-mediated STAT-1 activation occurs in two steps; 1) by impairing IFN secretion and 2) by induction of SOCS1. Taken together, our data implicate SOCS1 and type 1 interferons are novel target of GC in regulating STAT-1 activation for TLR-mediated inflammatory responses. Disclosures: Muglia: Pfizer Inc.: Research Funding.

Diabetes and osteoporosis

2011 ◽  
Vol 152 (29) ◽  
pp. 1161-1166 ◽  
Author(s):  
Zsuzsanna Valkusz
Keyword(s):  
Vitamin D ◽  
Type 1 Diabetes ◽  
Bone Mass ◽  
Fragility Fractures ◽  
Vitamin D Supplementation ◽  
Bone Collagen ◽  
Skeletal Changes ◽  
Glucagon Like Peptide 1 ◽  
Bone Quantity

Over the last decades a considerable amount of data has accumulated to indicate that metabolic and endocrine alterations of diabetes affect bone quantity and quality. These skeletal changes may increase the risk of bone fracture. There is strong evidence that in type 1 diabetes the decreased bone mass, lack of insulin and insulin-like growth factor-1, dysregulation of adipokines, and increased levels of proinflammatory cytokines are in the background of fragility fractures. In type 2 diabetes hyperinsulinemia, insulin resistance and increased body weight may result in an increase of bone mass; however, accumulation of advanced glycation end products within the bone collagen driven by glucotoxicity may increase the cortical porosity. There is a higher incidence of falls resulting from diabetes-related co-morbidities such as diabetic retinopathy, peripheral neuropathy, hypoglycemic episodes and sometimes from the medications. Vitamin D deficiency has special impact on glucose metabolism and the prevalence of diabetes. Vitamin D supplementation in childhood can decrease incidence of type 1 diabetes by 80%. The effect of thiazolidinediones, glucagon-like peptide-1 agonists and metformin, agents for treatment of diabetes open a new connection between bone, carbohydrate and fat metabolism. Orv. Hetil., 2011, 152, 1161–1166.

1964-P: Type 1 Diabetes: Sclerostin Resistance Improves Glucose Metabolism and Protects Bone Mass

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1964-P
Author(s):  
GIULIA LEANZA ◽  
YAEL ALIPPE ◽  
SEUNG-YON LEE ◽  
ROCKY STROLLO ◽  
PAOLO POZZILLI ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glucose Metabolism ◽  
Bone Mass ◽  
P Type

scholarly journals COVID-19 cardiac injury and the use of colchicine

2021 ◽  
Vol 14 (2) ◽  
pp. e241047
Author(s):  
Vanesa Anton-Vazquez ◽  
Laura Byrne ◽  
Lisa Anderson ◽  
Lisa Hamzah
Keyword(s):  
Sinus Tachycardia ◽  
Inflammatory Responses ◽  
Troponin T ◽  
Systolic Function ◽  
Cardiac Injury ◽  
T Wave ◽  
Wave Inversion ◽  
Ventricular Extrasystoles

We report a case of cardiac injury in a 46-year-old man affected by COVID-19. The patient presented with shortness of breath and fever. ECG revealed sinus tachycardia with ventricular extrasystoles and T-wave inversion in anterior leads. Troponin T and N-terminal pro B-type natriuretic peptide were elevated. Transthoracic echocardiography showed severely reduced systolic function with an estimated left ventricle ejection fraction of 30%. A nasopharingeal swab was positive for SARS-CoV-2. On day 6, 11 days after onset of symptoms, the patient deteriorated clinically with new chest pain and type 1 respiratory failure. Treatment with colchicine 0.5 mg 8-hourly resulted in rapid clinical resolution. This case report highlights how cardiac injury can dominate the clinical picture in COVID-19 infection. The role of colchicine therapy should be further studied to determine its usefulness in reducing myocardial and possibly lung parenchymal inflammatory responses.

Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Staley A. Brod
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Cognitive Decline ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Type I ◽  
Type I Ifn ◽  
Anti Inflammatory

Systemic inflammation is an organism’s response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer’s disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the “principal culprit” in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

Non-conventional signal transduction by type 1 interferons: The NF-κB pathway

2007 ◽  
Vol 102 (5) ◽  
pp. 1087-1094 ◽  
Author(s):  
Ziyun Du ◽  
Lai Wei ◽  
Aruna Murti ◽  
Susan R. Pfeffer ◽  
Meiyun Fan ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Conventional Signal ◽  
Type 1 Interferons

Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways

2021 ◽  
Vol 118 (45) ◽  
pp. e2107363118
Author(s):  
Ming-Wei Wang ◽  
Zhao Yang ◽  
Xu Chen ◽  
Shu-Hua Zhou ◽  
Ge-Lin Huang ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Leydig Cells ◽  
Inflammatory Responses ◽  
Mumps Virus ◽  
Related Protein ◽  
Parathyroid Hormone Receptor ◽  
Current Therapies ◽  
G Protein Coupled ◽  
Sperm Functions

Inflammation in the epididymis and testis contributes significantly to male infertility. Alternative therapeutic avenues treating epididymitis and orchitis are expected since current therapies using antibiotics have limitations associated to side effects and are commonly ineffective for inflammation due to nonbacterial causes. Here, we demonstrated that type 1 parathyroid hormone receptor (PTH1R) and its endogenous agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP), were mainly expressed in the Leydig cells of testis as well as epididymal epithelial cells. Screening the secretin family G protein–coupled receptor identified that PTH1R in the epididymis and testis was down-regulated in mumps virus (MuV)- or lipopolysaccharide (LPS)-induced inflammation. Remarkably, activation of PTH1R by abaloparatide (ABL), a Food and Drug Administration–approved treatment for postmenopausal osteoporosis, alleviated MuV- or LPS-induced inflammatory responses in both testis and epididymis and significantly improved sperm functions in both mouse model and human samples. The anti-inflammatory effects of ABL were shown to be regulated mainly through the Gq and β-arrestin-1 pathway downstream of PTH1R as supported by the application of ABL in Gnaq± and Arrb1−/− mouse models. Taken together, our results identified an important immunoregulatory role for PTH1R signaling in the epididymis and testis. Targeting to PTH1R might have a therapeutic effect for the treatment of epididymitis and orchitis or other inflammatory disease in the male reproductive system.

scholarly journals Higher levels of the soluble receptor for advanced glycation end products and lower levels of the extracellular newly identified receptor for advanced glycation end products were associated with lipid-lowering drugs in patients with type 1 diabetes: a comparative cross-sectional study

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Eva O. Melin ◽  
Jonatan Dereke ◽  
Magnus Hillman
Keyword(s):  
Type 1 Diabetes ◽  
Advanced Glycation End Products ◽  
Inflammatory Responses ◽  
Lipid Lowering ◽  
Advanced Glycation ◽  
Cross Sectional ◽  
Lipid Lowering Drugs ◽  
Glycation End Products ◽  
End Products

Abstract Background The receptors for advanced glycation end products (RAGE) are increased in atherosclerotic plaques. Soluble (s)RAGE decreases, whereas the extracellular newly identified receptor for advanced glycation end products (EN-RAGE) increases inflammatory responses mediated by RAGE. The aims were to explore whether sRAGE, EN-RAGE and the EN-RAGE/sRAGE ratio, were associated with the use of lipid-lowering drugs (LLD) and/or antihypertensive drugs (AHD) in patients with type 1 diabetes (T1D). Methods Cross-sectional design. T1D patients were consecutively recruited from one diabetes clinic. Blood samples were collected, supplemented with data from electronic health records. sRAGE and EN-RAGE were analysed by enzyme linked immunosorbent assays. An EN-RAGE/sRAGE ratio was calculated. Adjustments were performed with inflammatory and metabolic variables, s-creatinine, depression, smoking, physical inactivity, medication, and cardiovascular complications. Multiple regression analyses were performed. Results In this study 283 T1D patients (men 56%, 18–59 years) were included. One-hundred and thirty LLD users compared to 153 non-users had lower levels of the EN-RAGE/sRAGE ratio (P = 0.009), and 89 AHD users compared to 194 non-users had lower levels of sRAGE (P = 0.031). The use of LLD (inversely) (B coefficient − 0.158, P = 0.033) and the use of AHD (B coefficient 0.187, P = 0.023) were associated with the EN-RAGE/sRAGE ratio. sRAGE (Lg10) (per unit) (adjusted odds ratio (AOR) = 3.5, 95% CI = 1.4–9.1, P = 0.009), EN-RAGE (Lg10) (per unit) (inversely) (AOR 0.4, 95% CI = 0.2–1.0, P = 0.046), age (P <  0.001), and triglycerides (P <  0.029), were associated with LLD. sRAGE (Lg10) (per unit) (inversely) (AOR = 0.2, 95% CI = 0.1–0.5, P = 0.001), diabetes duration, triglycerides, s-creatinine, and systolic BP (all P values < 0.043), were associated with AHD. Conclusions Higher sRAGE levels and lower EN-RAGE levels were linked to the use of LLD, whereas lower sRAGE levels were linked to the use of AHD. No other variables but the use of LLD and the use of AHD were linked to the EN-RAGE/sRAGE ratio. This may be of major importance as sRAGE is an inhibitor and EN-RAGE is a stimulator of inflammatory processes mediated by RAGE.

A rapid and efficient method for generating anti-variable region monoclonal antibodies using type-1 interferons as immune modulators

2006 ◽  
Vol 15 (3) ◽  
pp. 61-69 ◽  
Author(s):  
Kimberly Staquet ◽  
Jamie Fisher ◽  
Roberta Lamb ◽  
Gregory Bannish ◽  
Cynthia Duchala ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Efficient Method ◽  
Variable Region ◽  
Immune Modulators ◽  
Type 1 Interferons
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