Extracts and auto-oxidized constituents of certain plants inhibit the receptor-binding and the biological activity of Graves' immunoglobulins.
Freeze-dried extracts (FDE) of the plants Lycopus virginicus, Lycopus europaeus, Melissa officinalis, and Lithospermum officinale, as well as products of the oxidation of certain of their constituents, have been shown to exert antithyrotropic activity by virtue of their ability to form adducts with TSH that bind weakly, if at all, to the TSH receptor. The thyroid-stimulating immunoglobulin G (IgG) found in the blood of patients with Graves' disease (Graves'-IgG) resemble TSH in their ability to bind to the thyroid plasma membrane, probably at the TSH receptor, and to activate the gland. In view of this similarity, and since some of the aforementioned FDE have been used in the treatment of hyperthyroidism in Graves' disease, we undertook studies of the effect of these FDE and their constituents on the binding and biological action of Graves'-IgG. In all samples of Graves'-IgG tested, incubation with antithyrotropic FDE or their antithyrotropic auto-oxidized constituents decreased their TSH-binding inhibitory activity in a dose-dependent manner. FDE from L. officinale also inhibited in a dose-dependent manner the direct binding to human thyroid membranes of a 125I-labeled preparation of receptor-purified Graves'-IgG. As judged from both stimulation of adenylate cyclase activity in vitro (thyroid-stimulating Ig activity) and enhancement of thyroid iodine release in the McKenzie assay system (LATS activity), antithyrotropic FDE and their auto-oxidized constituents also inhibited the biological responses to Graves'-IgG. FDE and constituents lacking antithyrotropic activity had little or no effect on the TSH-binding inhibitory activity, thyroid-stimulating Ig activity, or LATS activities of Graves'-IgG. Evidence of some degree of specificity of the inhibitory effects of the active compounds on Graves'-IgG was obtained in the demonstration that they failed to inhibit both the direct binding of [125I]insulin to its receptors in human lymphoblastoid IM-9 cells and the ability of IgG preparations containing antiinsulin receptor antibodies to inhibit the binding of labeled insulin. These observations suggest that the active principles in those FDE and their oxidized constituents with antithyrotropic activity may interact with the pathogenically important components of Graves'-IgG to inhibit their ability to bind to the TSH receptor and activate the thyroid, as they do with TSH. Our findings provide a possible rationale for the empirical, though poorly documented, use of FDE in the treatment of Graves' disease and some support for the suggestion that Graves'-specific IgG may have structural similarities to TSH itself.
Auf'mkolk
M
M
Ingbar
J C
JC
Kubota
K
K
Amir
S M
SM
Ingbar
S H
SH
D000262:Adenylyl Cyclases / Q000032:analysis; D006111:Graves Disease / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D010084:Oxidation-Reduction; D010936:Plant Extracts / Q000032:analysis / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011989:Receptors, Thyrotropin; D013961:Thyroid Gland / Q000378:metabolism; D013972:Thyrotropin / Q000037:antagonists & inhibitors / Q000378:metabolism
D007074:Immunoglobulin G; D007328:Insulin; D010936:Plant Extracts; D011956:Receptors, Cell Surface; D011989:Receptors, Thyrotropin; D013972:Thyrotropin; D000262:Adenylyl Cyclases