scholarly journals Osteostatin Inhibits Collagen-Induced Arthritis by Regulation of Immune Activation, Pro-Inflammatory Cytokines, and Osteoclastogenesis

2019 ◽  
Vol 20 (16) ◽  
pp. 3845 ◽  
Author(s):  
Josep Nácher-Juan ◽  
María Carmen Terencio ◽  
María José Alcaraz ◽  
María Luisa Ferrándiz
Keyword(s):  
T Cells ◽  
Bone Loss ◽  
Inflammatory Cytokines ◽  
T Cell Activation ◽  
Immune Activation ◽  
Joint Destruction ◽  
Related Protein ◽  
Collagen Induced Arthritis ◽  
Parathyroid Hormone Related Protein ◽  
Pro Inflammatory Cytokines

In chronic inflammatory joint diseases, such as rheumatoid arthritis, there is an important bone loss. Parathyroid hormone-related protein (PTHrP) and related peptides have shown osteoinductive properties in bone regeneration models, but there are no data on inflammatory joint destruction. We have investigated whether the PTHrP (107-111) C-terminal peptide (osteostatin) could control the development of collagen-induced arthritis in mice. Administration of osteostatin (80 or 120 μg/kg s.c.) after the onset of disease decreased the severity of arthritis as well as cartilage and bone degradation. This peptide reduced serum IgG2a levels as well as T cell activation, with the downregulation of RORγt+CD4+ T cells and upregulation of FoxP3+CD8+ T cells in lymph nodes. The levels of key cytokines, such as interleukin(IL)-1β, IL-2, IL-6, IL-17, and tumor necrosis factor-α in mice paws were decreased by osteostatin treatment, whereas IL-10 was enhanced. Bone protection was related to reductions in receptor activator of nuclear factor-κB ligand, Dickkopf-related protein 1, and joint osteoclast area. Osteostatin improves arthritis and controls bone loss by inhibiting immune activation, pro-inflammatory cytokines, and osteoclastogenesis. Our results support the interest of osteostatin for the treatment of inflammatory joint conditions.

scholarly journals Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α

2021 ◽  
Vol 22 (8) ◽  
pp. 3898
Author(s):  
Kenta Kaihara ◽  
Shuji Nakagawa ◽  
Yuji Arai ◽  
Hiroaki Inoue ◽  
Shinji Tsuchida ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cytokines ◽  
Joint Destruction ◽  
Hypoxia Inducible Factor ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Collagen Induced Arthritis ◽  
Risk Patients ◽  
Sustained Hypoxia ◽  
Pro Inflammatory Cytokines

Hypoxia inducible factor (HIF)-1α has been implicated in the pathogenesis of rheumatoid arthritis (RA). HIF-1α, which is expressed in hypoxia, is reversely suppressed in sustained hypoxia. Here, we investigated the inhibitory effect of hypoxia on arthritis by controlling HIF-1α. Rheumatoid fibroblast-like synoviocyte MH7A cells were cultured in a hypoxic incubator for up to 72 h to evaluate the expression of HIF-1. Furthermore, collagen-induced arthritis (CIA) model rats were maintained under 12% hypoxia in a hypoxic chamber for 28 days to evaluate the effect on arthritis. In MH7A cells, HIF-1α protein level increased at 3 h, peaked at 6 h, and subsequently decreased in a time-dependent manner. The transcription of pro-inflammatory cytokines increased at 1 h; however, they decreased after 3 h (p < 0.05). Deferoxamine-mediated activation of HIF-1α abolished the inhibitory effect of sustained hypoxia on pro-inflammatory cytokines. In the rat CIA model, the onset of joint swelling was delayed and arthritis was suppressed in the hypoxia group compared with the normoxia group (p < 0.05). Histologically, joint destruction was suppressed primarily in the cartilage. Thus, sustained hypoxia may represent a new safe, and potent therapeutic approach for high-risk patients with RA by suppressing HIF-1α expression.

Elevation of circulating plasma cytokines in cancer patients with high plasma parathyroid hormone-related protein levels.

2003 ◽  
pp. 403-407 ◽  
Author(s):  
S Takahashi ◽  
M Hakuta ◽  
K Aiba ◽  
Y Ito ◽  
N Horikoshi ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Inflammatory Cytokines ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
High Plasma ◽  
Tnf Alpha ◽  
Related Protein ◽  
Blood Concentrations ◽  
Parathyroid Hormone Related Protein ◽  
Pro Inflammatory Cytokines

Parathyroid hormone (PTH) and PTH-related protein/peptide (PTHrP) bind to the same PTH/PTHrP receptor and stimulate osteoblasts to secrete pro-inflammatory cytokines like interleukin (IL)-6. In patients with primary hyperparathyroidism, elevation of plasma levels of tumor necrosis factor (TNF)-alpha and IL-6 was also described. We, therefore, postulated that PTHrP secreted from cancer cells stimulates the secretion of cytokines and causes increases in their blood levels. Blood concentrations of several cytokines (TNF-alpha, IL-1beta, IL-5, IL-6, IL-8, IL-11 and IL-12) in cancer-bearing patients with or without elevation of blood PTHrP were measured by ELISA. The patients with high plasma PTHrP levels (n=29, intact PTHrP: 8.5 +/- 1.4 pmol/l, normal: <1.1) had higher serum type 1 collagen C-telopeptide (ICTP). Twenty of the patients were hypercalcemic. Plasma concentrations of TNF-alpha, IL-6 and IL-8 were significantly increased in patients with high PTHrP, in either the presence or absence of hypercalcemia. The concentrations of TNF-alpha and IL-6 were also significantly correlated with those of PTHrP. Our observations indicate that high plasma levels of PTHrP in cancer-bearing patients contribute not only to the development of hypercalcemia, but also to the development of the syndrome caused by an excess of pro-inflammatory cytokines.

scholarly journals Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

2021 ◽  
Vol 6 (57) ◽  
pp. eabf7570
Author(s):  
Laura A. Vella ◽  
Josephine R. Giles ◽  
Amy E. Baxter ◽  
Derek A. Oldridge ◽  
Caroline Diorio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Vascular Complications ◽  
Adult Disease ◽  
Vasoactive Medication ◽  
Inflammatory Syndrome

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

scholarly journals Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease

2021 ◽  
pp. annrheumdis-2020-219335
Author(s):  
Emma Garcia-Melchor ◽  
Giacomo Cafaro ◽  
Lucy MacDonald ◽  
Lindsay A N Crowe ◽  
Shatakshi Sood ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
T Cell Activation ◽  
Cell Activation ◽  
Conditioned Media ◽  
Tissue Remodelling ◽  
Activated T Cells ◽  
T Cell Migration

ObjectivesIncreasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation.MethodsT cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes.ResultsSignificant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte–T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio.ConclusionsInteraction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders.

Cinnamaldehyde and eugenol attenuates collagen induced arthritis via reduction of free radicals and pro-inflammatory cytokines

Phytomedicine ◽  
2019 ◽  
Vol 53 ◽  
pp. 70-78 ◽  
Author(s):  
Somaiya Mateen ◽  
Sumayya Shahzad ◽  
Shafeeque Ahmad ◽  
Syed Shariq Naeem ◽  
Saifullah Khalid ◽  
...  
Keyword(s):  
Free Radicals ◽  
Inflammatory Cytokines ◽  
Collagen Induced Arthritis ◽  
Pro Inflammatory Cytokines

Abstract 252: Interleukin-27 Signaling Regulates Myeloid Cells Activation in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Iuliia Peshkova ◽  
Aliia Fatkhullina ◽  
Ekaterina Koltsova
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Antigen Presenting Cells ◽  
Atherosclerotic Lesions ◽  
Mediators Of Inflammation ◽  
Antigen Presenting ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

Atherosclerosis is a lipid-driven inflammatory disease characterized by the progressive plaque growth in the vessels. Cytokines are important mediators of inflammation and atherosclerosis. While pro-inflammatory cytokines were extensively investigated, little is known about the role of anti-inflammatory cytokines as to their ability to control vascular inflammation. We tested whether immunoregulatory IL-27R signaling is important to control inflammation in mouse models of atherosclerosis. We found that atherosclerosis-prone mice with hematopoietic deficiency of IL-27R ( Ldlr -/- mice reconstituted with bone marrow from Il27ra -/- ) or global deficiency ( Il27ra -/- x Apoe -/- ) developed significantly larger atherosclerotic lesions compared to controls. Atherosclerotic lesions in IL-27R deficient mice contained more CD45 + leukocytes and CD4 + T cells, which produced pro-atherogenic cytokines IL-17A and TNF-α. These cytokines normally suppressed by IL-27, regulated the expression of CCL2 and other chemokines, which in turn led to accumulation of myeloid CD11b + and CD11c + cells in atherosclerotic aortas. Using two-photon microscopy, we found enhanced interactions between antigen presenting cells and T cells in the aortas of IL-27R deficient mice accompanied by enhanced CD4 T cell proliferation. Moreover, macrophages in Il27ra -/- aortas also demonstrated enhanced ability to produce pro-inflammatory cytokines, including IL-1. The blockade of IL-1R signaling, however, strongly suppressed atherosclerosis progression in IL-27R deficient but not control mice, suggesting an important role of IL-27 in the regulation of IL-1 production in atherosclerosis. Overall, our data demonstrate that IL-27R signaling in atherosclerosis is required to control function of antigen presenting cells modulating subsequent T cell activation in the aortas. Moreover, it controls macrophage activation and pro-inflammatory myeloid cell-derived cytokine production. These mechanisms altogether curb pathogenic T cell lineage differentiation and, thus, atherosclerosis, suggesting potent anti-atherogenic role of IL-27.

scholarly journals Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4+T Cell Activation during Antiretroviral Treatment

2014 ◽  
Vol 88 (14) ◽  
pp. 7818-7827 ◽  
Author(s):  
Sara Gianella ◽  
Marta Massanella ◽  
Douglas D. Richman ◽  
Susan J. Little ◽  
Celsa A. Spina ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Immune Activation ◽  
Genital Tract ◽  
Cell Activation ◽  
Future Studies ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Dna Reservoir

ABSTRACTAsymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is associated with increased immune activation and HIV disease progression. To determine the connections between CMV-associated immune activation and the size of the viral reservoir, we evaluated the interactions between (i) asymptomatic seminal CMV replication, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in blood from 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. We found that asymptomatic CMV shedding in semen was associated with significantly higher levels of proliferating and activated CD4+T cells in blood (P< 0.01). Subjects with detectable CMV in semen had approximately five times higher average levels of HIV DNA in blood CD4+T cells than subjects with no CMV. There was also a trend for CMV shedders to have increased cellular (multiply spliced) HIV RNA transcription (P= 0.068) compared to participants without CMV, but it is unclear if this transcription pattern is associated with residual HIV replication. In multivariate analysis, the presence of seminal plasma CMV (P= 0.04), detectable 2-long terminal repeat (2-LTR), and lower nadir CD4+(P< 0.01) were independent predictors of higher levels of proviral HIV DNA in blood. Interventions aimed at reducing seminal CMV and associated immune activation may be important for HIV curative strategies. Future studies of anti-CMV therapeutics will help to establish causality and determine the mechanisms underlying these described associations.IMPORTANCEAlmost all individuals infected with HIV are also infected with cytomegalovirus (CMV), and the replication dynamics of the two viruses likely influence each other. This study investigated interactions between asymptomatic CMV replication within the male genital tract, levels of inflammation in blood, and the size of the HIV DNA reservoir in 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. In support of our primary hypothesis, shedding of CMV DNA in semen was associated with increased activation and proliferation of T cells in blood and also significantly higher levels of HIV DNA in blood cells. These results suggest that CMV reactivation might play a role in the maintenance of the HIV DNA reservoir during suppressive ART and that it could be a target of pharmacologic intervention in future studies.

scholarly journals Loss of a Tyrosine-Dependent Trafficking Motif in the Simian Immunodeficiency Virus Envelope Cytoplasmic Tail Spares Mucosal CD4 Cells but Does Not Prevent Disease Progression

2012 ◽  
Vol 87 (3) ◽  
pp. 1528-1543 ◽  
Author(s):  
Matthew W. Breed ◽  
Andrea P. O. Jordan ◽  
Pyone P. Aye ◽  
Cornelis F. Lichtveld ◽  
Cecily C. Midkiff ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Progression ◽  
Simian Immunodeficiency Virus ◽  
Lamina Propria ◽  
T Cell Activation ◽  
Immune Activation ◽  
Cell Activation ◽  
Cytoplasmic Tail ◽  
Microbial Translocation ◽  
Immunodeficiency Virus

ABSTRACTA hallmark of pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections is the rapid and near-complete depletion of mucosal CD4+T lymphocytes from the gastrointestinal tract. Loss of these cells and disruption of epithelial barrier function are associated with microbial translocation, which has been proposed to drive chronic systemic immune activation and disease progression. Here, we evaluate in rhesus macaques a novel attenuated variant of pathogenic SIVmac239, termed ΔGY, which contains a deletion of a Tyr and a proximal Gly from a highly conserved YxxØ trafficking motif in the envelope cytoplasmic tail. Compared to SIVmac239, ΔGY established a comparable acute peak of viremia but only transiently infected lamina propria and caused little or no acute depletion of mucosal CD4+T cells and no detectable microbial translocation. Nonetheless, these animals developed T-cell activation and declining peripheral blood CD4+T cells and ultimately progressed with clinical or pathological features of AIDS. ΔGY-infected animals also showed no infection of macrophages or central nervous system tissues even in late-stage disease. Although the ΔGY mutation persisted, novel mutations evolved, including the formation of new YxxØ motifs in two of four animals. These findings indicate that disruption of this trafficking motif by the ΔGY mutation leads to a striking alteration in anatomic distribution of virus with sparing of lamina propria and a lack of microbial translocation. Because these animals exhibited wild-type levels of acute viremia and immune activation, our findings indicate that these pathological events are dissociable and that immune activation unrelated to gut damage can be sufficient for the development of AIDS.

Some mechanisms regulating nutrient utilisation in livestock during immune activation: an overview

2004 ◽  
Vol 44 (5) ◽  
pp. 453 ◽  
Author(s):  
I. G. Colditz
Keyword(s):  
Fatty Acid ◽  
Inflammatory Cytokines ◽  
Acute Phase ◽  
Immune Activation ◽  
Acute Phase Proteins ◽  
Tissue Injury ◽  
Acid Synthesis ◽  
Acid Uptake ◽  
Nutrient Utilisation ◽  
Pro Inflammatory Cytokines

The pro-inflammatory cytokines, IL-1, IL-6, TNFα and IFN α/β, produced during immune activation and tissue injury, override control of nutrient utilisation by the hypothalamic-somatotropic axis. The many effects of these cytokines include induction of fever and sickness behaviour, reduced fatty acid uptake by adipose tissue, reduced protein synthesis and enhanced protein breakdown in skeletal muscle, and gluconeogenesis, increased fatty acid synthesis and synthesis of acute phase proteins in the liver. Resistance to the effects of insulin, GH and IGF-1 is induced in adipose tissues, liver and muscle, at least in part through induction by pro-inflammatory cytokines of SOCS proteins which inhibit signal transduction and activation of gene transcription via the JAK/STAT pathway. These homeorhetic changes mobilise nutrients to fuel host defence responses. While an understanding of the mechanisms contributing to the catabolic state have arisen largely from studies of sepsis, trauma and acute challenge with biological mediators of the acute phase response, recent evidence in livestock suggests that graded production of pro-inflammatory cytokines during challenge with pathogens or subclinical infection can induce an incremental reduction in nutrient accretion in products of commercial value from livestock. This relationship highlights the value of good hygiene and reduced stress to improved feed utilisation for growth.

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