Methimazole and generation of oxygen radicals by monocytes: potential role in immunosuppression.

Weetman, A P; Holt, Mary E.; Campbell, Anthony K.; Hall, R.; McGregor, A M

doi:10.1136/bmj.288.6416.518

Cited by 97 publications

(35 citation statements)

References 10 publications

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“…Immune complexes associated with complement deposition have been observed on the thyroid follicular basement membrane (Werner et al, 1972;Kalderon & Bogaars, 1977) and the terminal component of complement, C9, has been detected at this site, implying formation of the membrane attack complex (MAC) of complement (Oleesky et al, 1986). We recently confirmed this by immunohistochemical staining of terminal complement complexes (TCC) around the thyroid follicles in Graves' disease and Hashimoto's thyroiditis, but not in normal glands (Weetman et al, 1989). Serum TCC concentrations were also elevated in these conditions and decreased with treatment of Graves' disease.…”

Section: Introductionsupporting

confidence: 64%

“…We have previously shown that TCC were elevated in the serum of patients with Hashimoto's thyroiditis and Graves' disease and decreased with anti-thyroid drug treatment (Weetman et al, 1989). TCC antigens were also detected immunohistochemically along the follicular basement membrane in autoimmune but not normal thyroid glands.…”

Section: Discussionmentioning

confidence: 98%

“…However, a variety of other destructive immunological processes, both humoral and cellular, operate in this condition (Weetman & McGregor, 1984;Burman & Baker, 1985) which suggests that the clinical outcome depends on the balance between thyroid stimulation and damage. Indeed, destructive hypothyroidism, similar to Hashimoto's thyroiditis, is a sequel to long-standing Graves' disease (Wood & Ingbar, 1979).…”

Section: Introductionmentioning

confidence: 99%

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Thyroid follicular cell function after non-lethal complement membrane attack

Weetman

Freeman

Morgan

1990

Clinical and Experimental Immunology

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SUMMARYTerminal complement complexes have been identified around thyroid follicles in Graves' disease and Hashimoto's thyroiditis, and the concentrations of such complexes are increased in the sera of these patients, suggesting a role for complement activation and membrane attack complexes (MAC) in autoimmune thyroiditis. This has been investigated further using cultured human and rat thyroid cells. Thyrocytes were resistant to lysis by homologous complement, in contrast to the effects of heterologous (rabbit) complement. The formation of non-lethal amounts of MAC, using reactive lysis or classical pathway activation, significantly reduced cAMP production by these cells in response to thyroid-stimulating hormone (TSH) (P< 0-01); similar effects were seen with thyroidstimulating antibodies. Thyroid cells were able to recover rapidly from complement attack after washing and incubation for 30 min. Non-lethal MAC formation also resulted in reactive oxygen metabolite production, detected by luminol-dependent chemiluminescence in three out offive thyroid cell preparations tested. Tonomycin, but not TSH, also stimulated reactive oxygen metabolite production. These results suggest that repeated or continuous sub-lethal complement attack on thyroid cells may exacerbate hypothyroidism in Hashimoto's thyroiditis, or partially counter the effects of thyroid-stimulating antibodies in Graves' disease. Furthermore, the production of reactive oxygen metabolites in these circumstances could increase the intra-thyroidal inflammatory response; oxygen radical scavenging by anti-thyroid drugs (which are concentrated by thyrocytes) may account in part for the amelioration of thyroiditis observed with such treatment.

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Section: Introductionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Thyroid follicular cell function after non-lethal complement membrane attack

Weetman

Freeman

Morgan

1990

Clinical and Experimental Immunology

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“…Consequently, depending on the degree of NADPH oxidase enzyme complex activity, a superoxide anion (O -2 ) is formed. An important factor determining the immunosuppressive action of thionamides, including methimazole, is the inhibition of the respiratory burst in resting monocytes and following their stimulation with PMA (38). In the study, no significant differences in the spontaneous NBT reduction test (modified RBA test) between groups C and E were found, although the stimulation with PMA, an activator of the free radical function, showed a lower oxygen activity of peripheral blood neutrophils in the group treated chronically with methimazole.…”

Section: Resultsmentioning

confidence: 52%

Influence of Beta-Endorphin on Oxygen Activity of Neutrophils and Total Antioxidant Status in Rats after Chronic Administration of Methimazole

Gołyński

Lutnicki

2013

Bulletin of the Veterinary Institute in Pulawy

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The aim of the study was to evaluate the effect of β-endorphin on oxygen activity of polimorphonuclear neutrophils and to investigate the total antioxidant status of blood serum in rats subjected to chronic treatment with methimazole. The study was carried out on 15 male Wistar rats weighing 270-290 g, divided into two groups. The animals from experimental group were administered a 0.05% drinking water solution of methimazole. The oxygen activity of peripheral blood neutrophils was examined using a modified RBA test. The extra-receptor effect of β-endorphin on the respiratory burst of neutrophils was evaluated. The incubation of neutrophils in the presence of phorbol myristate acetate (PMA) in the control group caused a nearly threefold increase in the oxygen activity of the cells compared to the control. Slightly higher values were obtained after addition of β-endorphin at the concentration of 10 -6 . Lower concentrations of this opioid (10 -8 and 10 -10 ) also stimulated oxygen activity but at a lower level than PMA. Naloxone did not affect the oxygen activity only when using β-endorphin in the concentration of 10 -6 . Naloxone and β-endorphin in the concentrations of 10 -8 and 10 -10 evoked a linear decrease in the oxygen activity of neutrophils, below the values obtained for PMA. The obtained results suggest that methimazole significantly modulates the generation of reactive oxygen species under the influence of β-endorphin, which stimulates the respiratory burst via the receptor pathway and inhibits it via the extra-cellular pathway. Methimazole also stimulates the anti-free radical defence.

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“…This suggests that oxidative alteration ofthe thyroid may play a role early in the development of the disease. Although increased free radical production in OS thyroids containing normal amounts ofiodine has yet to be demonstrated, thionamide drugs have been shown to decrease free radical formation (25)(26)(27). However, while this may explain the action of PTU, the effect of aminotriazole, a catalase inhibitor, cannot be explained by this mechanism.…”

Section: Discussionmentioning

confidence: 80%

Uptake and metabolism of iodine is crucial for the development of thyroiditis in obese strain chickens.

Brown¹,

Sundick²,

Dhar³

et al. 1991

J. Clin. Invest.

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To assess the importance of the role of thyroidal iodine in the pathogenesis of thyroiditis in the obese strain (OS) chicken, a model of spontaneous and severe disease, we studied the effect of antithyroid drugs that reduce thyroidal iodine or prevent its metabolism. Reduction of thyroidal iodine was achieved with KC104, an inhibitor of iodine transport and mononitrotyrosine (MNT), a drug that promotes loss of thyroidal iodine as iodotyrosines. A regimen consisting ofKC04 and MNT administration beginning in ovo and continuing after hatching reduced thyroidal infiltration to 2% of control values and decreased thyroglobulin antibody (TgAb) production for as long as 9 wk. Untreated birds had severe disease by 5 wk of age. The suppression of disease was independent of TSH, not mediated by generalized immunosuppression and reversed by excess dietary iodine. Two drugs that inhibit the metabolism of iodine, propylthiouracil (PTU) and aminotriazole, reduced thyroidal infiltration and TgAb levels, although to a lesser extent. When splenocytes from OS chickens with thyroiditis were transferred to Cornell strain (CS) chickens, a related strain that develops late onset mild disease, only the recipients that were iodine supplemented developed thyroiditis. In conclusion, autoimmune thyroiditis in an animal model can be prevented by reducing thyroidal iodine or its metabolism and optimal effects require intervention at the embryonic stage. (J. Clin. Invest.

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Methimazole and generation of oxygen radicals by monocytes: potential role in immunosuppression.

Cited by 97 publications

References 10 publications

Thyroid follicular cell function after non-lethal complement membrane attack

Thyroid follicular cell function after non-lethal complement membrane attack

Influence of Beta-Endorphin on Oxygen Activity of Neutrophils and Total Antioxidant Status in Rats after Chronic Administration of Methimazole

Uptake and metabolism of iodine is crucial for the development of thyroiditis in obese strain chickens.

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