Orbital Fibroblasts Exhibit a Novel Pattern of Responses to Proinflammatory Cytokines: Potential Basis for the Pathogenesis of Thyroid-Associated Ophthalmopathy

Human orbital fibroblasts are more susceptible to some actions of proinflammatory cytokines than are fibroblasts from other anatomic regions. These cells produce high levels of PGE2when activated by cytokines. Here we report that they express high levels of prostaglandin-endoperoxide H synthase (PGHS)-2, the inflammatory cyclooxygenase, when treated with IL-1β. This induction results from enhanced PGHS-2 mRNA stability and small increases in gene promoter activity. The enhanced transcript stability is a result of actions of the cytokine on the 3′-untranslated region. Orbital fibroblasts, unlike those from skin, fail to express high levels of IL-1 receptor antagonist (IL-1ra) when treated with IL-1β, leading to loss of modulation of IL-1 action. This can be overcome by transiently transfecting cells with IL-1ra. Thus a decreased level of IL-1ra expression in orbital fibroblasts may underlie the exaggerated responses to IL-1 observed in those cells and, therefore, the susceptibility of the orbit to inflammation.

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

AJP Cell Physiology ◽

10.1152/ajpcell.1998.274.3.c707 ◽

1998 ◽

Vol 274 (3) ◽

pp. C707-C714 ◽

Cited By ~ 100

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.

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Antibodies to orbital tissues in thyroid-associated ophthalmopathy

Acta Endocrinologica ◽

10.1530/acta.0.1260137 ◽

1992 ◽

Vol 126 (2) ◽

pp. 137-142 ◽

Cited By ~ 8

Author(s):

Petros Perros ◽

Pat Kendall-Taylor

Keyword(s):

Autoimmune Diseases ◽

Extraocular Muscle ◽

Enzyme Linked Immunosorbent Assay ◽

Eye Muscle ◽

Autoimmune Attack ◽

Thyroid Associated Ophthalmopathy ◽

Binding Antibody ◽

Antibody Levels ◽

Orbital Fibroblasts ◽

Normal Controls

Thyroid-associated ophthalmopathy is thought to be an autoimmune disease affecting the orbit. The precise pathogenetic mechanisms are not known, but extraocular muscle and/or orbital fibroblasts are the likely targets of the autoimmune attack. Sera from 41 normal controls, 79 patients with thyroid-associated ophthalmopathy and 72 patients with other autoimmune diseases were examined for antibodies to cultured orbital fibroblasts and extraocular muscle by enzyme-linked immunosorbent assay. Orbital fibroblast antibody levels varied widely in all subject groups studied, and failed to distinguish patients with thyroid-associated ophthalmopathy from patients with other autoimmune diseases or controls. Eye-muscle binding antibody levels were higher amongst patients with ophthalmopathy compared to normal controls and patients with Graves' hyperthyroidism without clinical evidence of ophthalmopathy. Furthermore, eye-muscle binding antibody levels were found to be particularly high in patients with ophthalmopathy and concurrent dermopathy, and in patients with ophthalmic (euthyroid) Graves' disease.

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

Journal of Molecular Endocrinology ◽

10.1530/jme-17-0276 ◽

2018 ◽

Vol 61 (1) ◽

pp. T29-T43 ◽

Cited By ~ 14

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.

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