Phenotypic Attributes of Orbital Fibroblasts Underlie Their Susceptibility in Graves’ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complex Activities of Human Fibroblasts are

2005 ◽  
pp. 189-202 ◽  
Keyword(s):  
Human Fibroblasts ◽  
Graves Disease ◽  
Disease Complex ◽  
Orbital Fibroblasts ◽  
Complex Activities

scholarly journals Human orbital fibroblasts are activated through CD40 to induce proinflammatory cytokine production

1998 ◽  
Vol 274 (3) ◽  
pp. C707-C714 ◽  
Author(s):  
Gregory D. Sempowski ◽  
Julia Rozenblit ◽  
Terry J. Smith ◽  
Richard P. Phipps
Keyword(s):  
T Lymphocytes ◽  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
Human Fibroblasts ◽  
Clinical Problem ◽  
Cd40 Ligand ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Thyroid Associated Ophthalmopathy ◽  
Orbital Fibroblasts

CD40 is an important signaling and activation antigen found on certain bone marrow-derived cells. Recently, CD40 has also been shown to be expressed by nonhematopoietic cells, including certain human fibroblasts, but not others. Little is known about the function of CD40 on fibroblasts. The current study investigates the hypothesis that CD40 is expressed on orbital fibroblasts and represents a pathway for interaction between these fibroblasts and CD40 ligand-expressing cells, such as T lymphocytes and mast cells. We report here that orbital connective tissue fibroblasts, obtained from normal donors and from patients with severe thyroid-associated ophthalmopathy (TAO), express functional CD40. CD40 is upregulated ∼10-fold by interferon-γ (500 U/ml) treatment for 72 h. These fibroblasts become activated through triggering of CD40 with CD40 ligand (CD40L). This is evidenced by nuclear translocation of nuclear factor-κB and induction of the proinflammatory and chemoattractant cytokines interleukin-6 and interleukin-8, respectively. These data support the concept that cognate interactions between orbital fibroblasts and infiltrating T lymphocytes, via the CD40-CD40L pathway, may promote the tissue remodeling observed in TAO and other inflammatory diseases of the orbit. Disruption of the CD40-CD40L interaction may represent a therapeutic intervention to reduce the inflammatory components of TAO, which remains a vexing clinical problem.

scholarly journals Fucoxanthin improves functional recovery of orbitopathy in Graves’ disease by downregulating IL-17 mRNA expression in a mouse model

2020 ◽  
Vol 19 (5) ◽  
pp. 933-941
Author(s):  
Lichao Chai ◽  
Jing Wang ◽  
Yan Wei
Keyword(s):  
Mrna Expression ◽  
Graves Disease ◽  
Oxidative Potential ◽  
Stress Markers ◽  
Tnf Α ◽  
Anti Oxidant ◽  
Graves Orbitopathy ◽  
Orbital Fibroblast ◽  
Complete Cell ◽  
Orbital Fibroblasts

Purpose: To explore the efficacy of fucoxanthin (FX), a carotenoid, against inflammation via inhibition of IL-17 mRNA expression, and its anti-oxidant activity in Graves’ orbitopathy (GO)-induced mice model.Methods: The effects of FX on IL-6, IL-8, IL-17, MCP-1, and TNF-α, in orbital fibroblast tissues extracted from GO-induced BALB/c mice was  investigated. Anti-oxidative stress markers, 8-hydroxy-2’- deoxyguanosine (8-OHdG) and malondialdehyde (MDA) levels were quantified in tear samples collected from GO-induced FX treated mice.Results: FX administration in cultured human orbital fibroblast cells revealed almost complete cell viability and no cell apoptosis. FX resulted in IL-1β induced Beclin-1 and Atg-5 silencing, in cultured human orbital fibroblasts. BALB/c mice immunized with Ad-TSHR289 indicated elevated levels ofthyroid peroxidase and thyroglobulin antibodies in the serum sample. FX predominantly downregulated the mRNA expression of IL-17, and also reduced increased 8-OHdG and MDA in the tear secretion of GO-induced mice.Conclusion: FX may be an effective and useful molecule for the treatment of GO, through its antiinflammatory and anti-oxidative potential, but it requires further investigation to ascertain its therapeutic effectiveness. Keywords: Anti-inflammatory, Anti-oxidant, Fucoxanthin, Graves’ disease, Graves’ orbitopathy, IL-17

scholarly journals 40 YEARS OF IGF1: IGF1 receptor and thyroid-associated ophthalmopathy

2018 ◽  
Vol 61 (1) ◽  
pp. T29-T43 ◽  
Author(s):  
Michelle Mohyi ◽  
Terry J Smith
Keyword(s):  
Graves Disease ◽  
Physical Interaction ◽  
Therapeutic Trial ◽  
Thyrotropin Receptor ◽  
Autoimmune Process ◽  
The Past ◽  
Thyroid Associated Ophthalmopathy ◽  
Upper Face ◽  
Igf1 Receptor ◽  
Orbital Fibroblasts

Thyroid-associated ophthalmopathy (TAO) is a vexing and poorly understood autoimmune process involving the upper face and tissues surrounding the eyes. In TAO, the orbit can become inflamed and undergo substantial remodeling that is disfiguring and can lead to loss of vision. There are currently no approved medical therapies for TAO, the consequence of its uncertain pathogenic nature. It usually presents as a component of the syndrome known as Graves’ disease where loss of immune tolerance to the thyrotropin receptor (TSHR) results in the generation of activating antibodies against that protein and hyperthyroidism. The role for TSHR and these antibodies in the development of TAO is considerably less well established. We have reported over the past 2 decades evidence that the insulin-like growth factorI receptor (IGF1R) may also participate in the pathogenesis of TAO. Activating antibodies against IGF1R have been detected in patients with GD. The actions of these antibodies initiate signaling in orbital fibroblasts from patients with the disease. Further, we have identified a functional and physical interaction between TSHR and IGF1R. Importantly, it appears that signaling initiated from either receptor can be attenuated by inhibiting the activity of IGF1R. These findings underpin the rationale for therapeutically targeting IGF1R in active TAO. A recently completed therapeutic trial of teprotumumab, a human IGF1R inhibiting antibody, in patients with moderate to severe, active TAO, indicates the potential effectiveness and safety of the drug. It is possible that other autoimmune diseases might also benefit from this treatment strategy.

Human orbital fibroblasts in culture bind and respond to endothelin

1993 ◽  
Vol 265 (1) ◽  
pp. C138-C142 ◽  
Author(s):  
T. J. Smith ◽  
R. J. Kottke ◽  
H. Lum ◽  
T. T. Andersen
Keyword(s):  
Binding Capacity ◽  
Human Fibroblasts ◽  
Cellular Protein ◽  
Binding Activity ◽  
Dermal Fibroblasts ◽  
Acetoxymethyl Ester ◽  
Single Class ◽  
Free Concentration ◽  
Amino Acid Peptide ◽  
Orbital Fibroblasts

Human fibroblasts in primary cell culture were studied for their ability to bind to endothelin (ET), a 21-amino acid peptide with profound vasoconstricting properties. When 125I-labeled ET-1 was incubated with confluent orbital fibroblasts in the presence of increasing concentrations of unlabeled ligand, a single class of binding site was defined with a dissociation constant of 1.42 x 10(-8) M and a maximal binding capacity of 9.1 x 10(-10) mol/micrograms protein. ET-3 was a substantially less potent competitor for 125I-ET-1 binding sites than was unlabeled ET-1. Dermal fibroblasts demonstrated approximately 75% less ET-1 saturation binding activity, on a cellular protein basis, than did those from the orbit. Orbital fibroblasts responded to ET-1 (10(-9) M) with a rapid and transient increase in the free concentration of intracellular Ca2+ ([Ca2+]i) as assessed by monitoring acetoxymethyl ester of fura 2 fluorescence intensity. Rechallenge with the peptide elicited a substantially attenuated response than that seen after the initial treatment. There was no consistent effect of ET-1 on [Ca2+]i in dermal cultures. ET-3 failed to influence [Ca2+]i in either type of fibroblast. It would appear that orbital fibroblasts bind and respond to ET in a manner distinct from that observed in dermal fibroblasts, raising the possibility that the peptide may have site-specific actions in orbital connective tissue.

scholarly journals The Role of Oxidative Stress on the Pathogenesis of Graves' Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Miloš Žarković
Keyword(s):  
Oxidative Stress ◽  
The Other ◽  
Graves Disease ◽  
Graves Ophthalmopathy ◽  
Selenium Treatment ◽  
Graves Orbitopathy ◽  
Eye Involvement ◽  
Orbital Fibroblasts

Graves' disease is a most common cause of hyperthyroidism. It is an autoimmune disease, and autoimmune process induces an inflammatory reaction, and reactive oxygen species (ROSs) are among its products. When balance between oxidants and antioxidants is disturbed, in favour of the oxidants it is termed “oxidative stress” (OS). Increased OS characterizes Graves' disease. It seems that the level of OS is increased in subjects with Graves' ophthalmopathy compared to the other subjects with Graves' disease. Among the other factors, OS is involved in proliferation of orbital fibroblasts. Polymorphism of the 8-oxoG DNA N-glycosylase 1 (hOGG1) involved in repair of the oxidative damaged DNA increases in the risk for developing Grave's disease. Treatment with glucocorticoids reduces levels of OS markers. A recent large clinical trial evaluated effect of selenium on mild Graves' ophthalmopathy. Selenium treatment was associated with an improved quality of life and less eye involvement and slowed the progression of Graves' orbitopathy, compared to placebo.

scholarly journals Novel anti-adipogenic activity produced by human fibroblasts

2010 ◽  
Vol 299 (3) ◽  
pp. C672-C681 ◽  
Author(s):  
Geniece M. Lehmann ◽  
Collynn F. Woeller ◽  
Stephen J. Pollock ◽  
Charles W. O'Loughlin ◽  
Shikha Gupta ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Human Fibroblasts ◽  
Fat Deposition ◽  
Health Concern ◽  
Fatty Tissue ◽  
Cellular Expression ◽  
Flow Cytometric ◽  
Treatment Of Obesity ◽  
Orbital Fibroblasts ◽  
Do So

Fatty tissue is generally found in distinct “depots” distributed throughout the human body. Adipocytes from each of the various depots differ in their metabolic capacities and their responses to environmental stimuli. Although a general understanding of the factors responsible for adipogenic transformation has been achieved, much is not understood about the mechanisms of adipose tissue deposition and the phenotypes of the adipocytes found within each depot. A clue to the factors regulating fat deposition may come from studies of adipogenesis using primary human orbital fibroblasts from patients with thyroid eye disease, a condition in which intense inflammation leads to expansion of orbital adipose tissue via differentiation of fibroblasts to adipocytes. We have previously demonstrated that adipogenesis of orbital fibroblasts is negatively correlated with cellular expression of the Thy-1 surface marker. In this study, we developed a novel imaging flow cytometric approach for the assessment of adipogenesis to test the hypothetical dependence of adipogenic potential on lack of Thy-1 expression. Using this technique, we learned that Thy-1-positive fibroblasts are, in fact, capable of differentiating into adipocytes but are less likely to do so because they secrete a paracrine anti-adipogenic factor. It is possible that such a factor plays an important role in the prevention of excess fat deposition in the normal orbit and may even be exploited as a therapy for the treatment of obesity, a major worldwide health concern.

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