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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 1 121-124
Copyright © 1998 by The Endocrine Society

Original Studies

Nicotinamide Decreases Cytokine-Induced Activation of Orbital Fibroblasts from Patients with Thyroid-Associated Ophthalmopathy

Yuji Hiromatsu, Damu Yang, Ikuyo Miyake, Mari Koga, Junko Kameo, Masayuki Sato, Yoichi Inoue and Kyohei Nonaka

Division of Endocrinology and Metabolism (Y.H., D.Y., I.M., M.K., J.K., M.S., K.N.), Department of Medicine, Kurume University School of Medicine, Fukuoka, 830 Japan; and Eye Division of Olympia Clinic (Y.I.), 150 Tokyo, Japan

Address all correspondence and requests for reprints to: Dr. Yuji Hiromatsu, Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830 Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We used flow cytometry to investigate the effects of nicotinamide, an inhibitor of poly (ADP ribose) synthetase, on the cell-surface expression of cytokine-induced human leukocyte antigen (HLA)-A,B,C antigen, HLA-DR antigen, intercellular adhesion molecule 1, CD44, and Fas expression in cultured orbital fibroblasts from patients with thyroid-associated ophthalmopathy. After two to seven passages, cultured orbital fibroblasts were incubated for 3 days with interferon {gamma} or tumor necrosis factor {alpha} in the presence of nicotinamide. Nicotinamide inhibited the induction of both HLA-DR and intercellular adhesion molecule 1 expression by cytokines on fibroblasts but did not interfere with induction of HLA-A,B,C, or CD44 expression. Nicotinamide also inhibited the proliferation of orbital fibroblasts, as assessed by a [3H]-thymidine incorporation assay and cell counts. Nicotinamide also enhanced the expression of the apoptosis-mediating protein Fas on fibroblasts. Our data suggest that nicotinamide inhibits cytokine-induced activation of fibroblasts and thus may decrease the autoimmune injury to the orbit in thyroid-associated ophthalmopathy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THYROID-ASSOCIATED ophthalmopathy (TAO) is considered generally to be an autoimmune disorder in which enlargement of extraocular muscles and an increased volume of orbital fat are prominent characteristics (1, 2, 3). Marked lymphocytic infiltration and inflammatory cytokines, such as interferon (IFN) {gamma}, interleukin 1, and tumor necrosis factor (TNF) {alpha}, have been detected in active-stage orbital lesions (4, 5, 6). Aberrant expression of human leukocyte antigen (HLA)-DR on fibroblasts has been implicated in the development of TAO (2); in addition, the expression of various adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and CD44 on orbital fibroblasts, are reportedly involved in the migration of lymphocytes to inflammatory sites in the orbit (7, 8). The expression of these adhesion molecules and HLA-DR is induced by the inflammatory cytokines. These results suggest that activation of orbital fibroblasts may play a major role in the development of TAO.

Nicotinamide, an inhibitor of poly (ADP ribose) synthetase, has been shown to inhibit the development of diabetes in nonobese diabetic mice (9) and in humans (10, 11), although responsible mechanisms are not clear. We previously have reported that nicotinamide suppressed cytokine-induced major histocompatibility complex (MHC) class II antigen expression on normal mouse islet cells (12), human umbilical endothelial cells (13), and human thyroid cells (14). Furthermore, we have reported that nicotinamide inhibited the induction of ICAM-1 on endothelial cells and thyroid cells (15).

In the present study, we investigated the effects of nicotinamide on cytokine-induced HLA-DR, ICAM-1, and CD44 expression on cultured human orbital fibroblasts derived from surgical specimens from patients with TAO. We also studied the effects of nicotinamide on Fas expression, which mediates apoptosis of various cells (16), as well as the proliferation of cultured orbital fibroblasts.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Orbital fat was obtained at orbital decompression surgery from four patients with TAO and three patients with absolute glaucoma at surgery for enucleation of the eye ball. Subcutaneous fat was obtained from the neck in the course of surgery for Graves’ disease in four patients and follicular thyroid adenoma in three patients. Fibroblasts were cultured as previously reported (17). Briefly, adipose tissue was minced and placed in DMEM, supplemented with 10% FBS, on a tissue culture dish. After two to eight passages, cultured fibroblasts (approximately 1–2 x 104/well in 24-well plates) were cultured further with recombinant human IFN{gamma} (Mallinckrodt Inc., Paris, KY) or TNF{alpha} (R&D Systems, Minneapolis, MN) in the presence of various concentrations of nicotinamide (SIGMA, St. Louis, Mo; 1–40 mmol/L) for 3 days at 37 C in a humidified atmosphere of 5% CO2. After explanation of the nature of the study, informed consent was obtained by the authors for the donation of orbital fat from patients with TAO and subcutaneous fat from control subjects.

To detect cell-surface molecules such as HLA-A,B,C, HLA-DR, ICAM-1, CD44, and Fas, cultured cells were treated with 0.05% trypsin and 0.02% EDTA solution and incubated with mouse monoclonal antibody against HLA-A,B,C (Dako-HLA-ABC: Dakopatts A/S, Glostrup, Denmark), HLA-DR (Ortho-mune OKDR: Ortho Diagnostic Systems; Raritan, NJ), ICAM-1 (anti-ICAM-1 antibody: Immunotech, Marseilles, France), CD44 (MEM-85: IgG1, Nichirei, Tokyo, Japan), and Fas (IgG1, Medical and Biological Laboratories, Nagoya, Japan) at 1:50–100 dilution or with negative control mouse monoclonal antibody (IgG1, IgG2: Dako) at a 1:50 dilution for 30 min on ice. After washing with PBS, the cells were incubated for 30 min on ice with fluorescein isothiocyanate-conjugated rabbit IgG F(ab')2 directed against heavy and light chains of mouse IgG (Wako Pure Chemical Industries, Osaka, Japan) at a 1:50 dilution. After a final wash, the cells were analyzed by flow cytometry (Ortho Cytron, Ortho Diagnostic Systems). The cells were counted for 120 sec or up to a minimum of 5,000 cells. Percentages of positive cells and mean fluorescence intensity were determined. Fibroblasts whose immunofluorescence intensity was greater than that of fibroblasts stained with negative control mouse monoclonal antibody were classified as positive.

Proliferation of fibroblasts was estimated by [3H]-thymidine in-corporation assays, as described previously (10, 11). Briefly, orbital fibroblasts were cultured for 5 days with various concentrations of nicotinamide. Twenty-four hours before termination, 0.1 µCi of [3H]-thymidine was added to each well. The cells were harvested by a semiautomatic harvester (Labo Mash, Labo Science, Tokyo, Japan). The radioactivity of each sample was determined in a liquid scintillation counter. The proliferation of fibroblasts also was investigated using a cell counting kit (Dojindo Laboratories, Kumamoto, Japan), according to the manufacture’s instructions. Briefly, fibroblasts in a 96-well plate, cultured with nicotinamide for 5 days, were further cultured with 0.5 mmol/L WST-1, 0.02 mmol/L 1-methoxy PMS, 2 mmol/L HEPES for 1 h, after which optical density was measured at 450 nm using an automatic spectrophotometer (EIA reader; Bio-Rad, Hercules, CA). Statistical analysis was carried out using paired Student’s t test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The effects of nicotinamide on IFN{gamma}-induced HLA-A,B,C, and HLA-DR expression on orbital fibroblasts from patients with TAO

HLA-DR and HLA-A,B,C antigens were expressed in 2.0 ± 2.3% and 84.3 ± 16.1%, respectively, of human orbital fibroblasts from patients with TAO. IFN{gamma} induced HLA-DR and HLA-A,B,C expression on the surface of orbital fibroblasts in a dose-dependent manner (10–400 U/mL, data not shown). Nicotinamide inhibited the HLA-DR expression induced by IFN{gamma} in a dose-dependent manner (Fig. 1AGo) but not HLA-A,B,C expression (Fig. 1BGo).



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  		Figure 1. Effect of nicotinamide on IFN{gamma}-induced HLA-DR (A) and HLA-A,B,C expression (B) on orbital fibroblasts. Orbital fibroblasts were cultured for 3 days in medium alone or in the presence of 200 U/mL recombinant human IFN{gamma} and various concentrations of nicotinamide (0–20 mmol/L). Cells were evaluated for HLA-DR and HLA-A,B,C expression using monoclonal antibodies to HLA-DR and HLA-A,B,C, followed by FITC-conjugated rabbit IgG F(ab')2 against mouse IgG (H+L) for flow cytometry. Results were expressed as the mean (±SD) percentage of cells positive in three experiments using orbital fibroblasts obtained from different patients. *, P < 0.05.

 
The effects of nicotinamide on TNF{alpha}-induced ICAM-1 and CD44 expression on orbital fibroblasts from patients with TAO

Nicotinamide inhibited the ICAM-1 expression induced by TNF{alpha} in a dose-dependent manner. The percentage (±SD) of ICAM-1-positive cells in culture with 20 mmol/L nicotinamide was significantly smaller than that in the absence of nicotinamide (18.4 ± 7.1% vs. 40.5 ± 13.5%, respectively, P < 0.05, Fig. 2AGo). On the other hand, TNF{alpha}-induced CD44 expression was not affected by nicotinamide (Fig. 2BGo).



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  		Figure 2. Effect of nicotinamide on TNF{alpha}-induced ICAM-1 (A) and CD44 expression (B) on orbital fibroblasts. Orbital fibroblasts were treated with increasing doses of nicotinamide in the presence of TNF{alpha} (10 U/mL) for 3 days. Cells were evaluated for ICAM-1 and CD44 expression using monoclonal antibodies to ICAM-1 and CD44, respectively, followed by FITC-conjugated rabbit IgG F(ab')2 against mouse IgG (H+L) for flow cytometry. Results were expressed as the mean (±SD) percentage of cells positive in three experiments using orbital fibroblasts obtained from different patients. *, P < 0.05.

 
The effects of nicotinamide on Fas expression on orbital fibroblasts from patients with TAO

Although IFN{gamma} induced Fas expression on fibroblasts, nicotinamide itself induced Fas expression on orbital fibroblasts in a dose-dependent manner (Fig. 3Go).



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  		Figure 3. Effect of nicotinamide on Fas expression on orbital fibroblasts. Orbital fibroblasts were treated with increasing doses of nicotinamide for 3 days. Cells were evaluated for Fas expression using monoclonal antibody to Fas. See text for details. *, P < 0.05.

 
The effects of nicotinamide on the proliferation of orbital fibroblasts from patients with TAO

As shown in Fig. 4Go, nicotinamide significantly inhibited the proliferation of orbital fibroblasts, as assessed by the [3H]-thymidine incorporation assay (Fig. 4AGo) and cell counting method (Fig. 4BGo).



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  		Figure 4. Effect of nicotinamide on the proliferation of orbital fibroblasts. Orbital fibroblasts were cultured with or without nicotinamide for 5 days and then assessed as follows: A, DNA synthesis in orbital fibroblasts as determined by [3H]-thymidine incorporation; B, cell counts, assessed by a cell counting kit. See text for details. Each point represents the mean (±SD) values of three experiments. *, P < 0.05.

 
The effects of nicotinamide on the proliferation of orbital fibroblasts from control subjects

To investigate whether the effects of nicotinamide on HLA-DR, ICAM-1, and Fas expression and proliferation of orbital fibroblasts are specific to the patients with TAO, we repeated the experiments, using orbital fibroblasts from control subjects. Nicotinamide inhibited the IFN{gamma}-induced HLA-DR expression (IFN{gamma} 200 U/mL, 63.3 ± 25.3%; IFN{gamma} 200 U/mL and nicotinamide 20 mmol/L, 31.3 ± 24.3%, P < 0.05) and TNF{alpha}-induced ICAM-1 expression (TNF{alpha} 100 U/mL, 35.5 ± 5.2%; TNF{alpha} 100 U/mL and nicotinamide 10 mmol/L, 23.0 ± 1.3%, P < 0.05). On the other hand, nicotinamide enhanced the Fas expression (basal, 9.6 ± 3.0%; nicotinamide 20 mmol/L, 19.4 ± 3.9%, P < 0.05) and suppressed the proliferation of fibroblasts (basal OD, 0.66 ± 0.04; nicotinamide 40 mmol/L, 0.35 ± 0.02, P < 0.01).

The effects of nicotinamide on skin fibroblasts

To determine whether the effects of nicotinamide on the expression of HLA-DR, ICAM-1, Fas, and the proliferation of fibroblasts are specific to the orbital fibroblasts, we repeated the experiments, using skin fibroblasts from patients with TAO and normal subjects. Nicotinamide again inhibited the induction of HLA-DR and ICAM-1 expression on skin fibroblasts from patients (Fig. 5Go, A and B) or control subjects (data not shown). A little enhancement of Fas expression on skin fibroblasts by nicotinamide was noted (Fig. 5CGo). Nicotinamide also inhibited proliferation of these fibroblasts (Fig. 5DGo).



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  		Figure 5. Effect of nicotinamide on IFN{gamma}-induced HLA-DR expression (A), TNF{alpha}-induced ICAM-1 expression (B), and Fas expression on skin fibroblasts (C); and proliferation of skin fibroblasts (D). See text for details. *, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Nicotinamide, a potent inhibitor of poly (ADP ribose) synthetase, which is involved in DNA repair (18), cell differentiation (19), and transcription (20), have been shown to prevent alloxan- or streptozotocin-induced diabetes (21) and also autoimmune-associated diabetes in NOD mice (9) and humans (10, 11). We recently have reported that nicotinamide inhibited the induction of MHC class II antigen expression on normal mouse islet cells (9), human endothelium (10, 11), and human thyroid cells (14) by IFN{gamma}, as well as ICAM-1 expression on human endothelial cells (13) and thyroid cells (15). In the present study, we demonstrated the inhibitory effect of nicotinamide on HLA-DR and ICAM-1 expression on cultured human orbital fibroblasts but not on HLA-A,B,C or CD44. However, it still remains to be clarified whether the inhibition of cytokine-induced HLA-DR and ICAM-1 expression on orbital fibroblasts is related to the prevention of nicotinamide adenine dinucleotide depletion, free-radical scavenging, or unknown mechanisms. The failure of superoxide dismutase and catalase, both free-radical scavengers, to inhibit expression of HLA-DR and ICAM-1 on endothelial and thyroid cells (13, 14, 15) suggests that the inhibition of HLA-DR and ICAM-1 induction by nicotinamide on fibroblasts may not be related to free-radical scavenging.

There are several lines of evidence that the expression of HLA-DR and ICAM-1 on orbital fibroblasts may play important roles in the pathogenesis of TAO (2, 7). HLA-DR and ICAM-1 are expressed more in vivo in orbital tissue from patients with TAO than in control orbital tissue. ICAM-1 expression and ICAM-1-mediated lymphocyte binding are induced by IFN{gamma} (22). Because ICAM-1 is involved in directing lymphocytes from the blood to inflammatory sites and also augments immune processes, such as antigen presentation and cytotoxicity (23), the suppression of ICAM-1 expression on orbital fibroblasts by nicotinamide may reduce the inflammatory reactions associated with TAO.

Fas-mediated apoptosis, a type of cell death, is involved in control of cell proliferation. Fas ligand is expressed in activated T cells, and Fas expression is enhanced by various inflammatory cytokines (16). We previously have reported the presence of Fas ligand and Fas expression in the orbital tissue from patients with TAO (24). In the present study, we demonstrated that the expression of Fas on orbital fibroblasts was enhanced by nicotinamide. Further study is indicated to clarify whether nicotinamide induces apoptosis of activated fibroblasts. We demonstrated that nicotinamide suppresses proliferation of orbital fibroblasts.

In conclusion, nicotinamide inhibits cytokine-induced HLA-DR and ICAM-1 induction on fibroblasts, as well as proliferation of these cells, although the effects were not specific to orbital fibroblasts from patients with TAO. Further studies are indicated to elucidate whether the suppressive effect of nicotinamide on HLA-DR and ICAM-1 expression and proliferation of orbital fibroblasts may be useful in preventing ophthalmopathy or treating TAO.


   Acknowledgments
 
We thank Professor M. Mochizuki (Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan) and Dr. N. Koike (Koike Hospital, Saga, Japan) for providing orbital fat tissue from control subjects and subcutaneous fat tissue, respectively.

Received November 26, 1996.

Revised May 16, 1997.

Accepted July 25, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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