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Cyclooxygenase-Dependent Thyroid Cell Proliferation Induced by Immunoglobulins from Patients with Graves’ Disease¹

Division of Endocrinology (R.D.P., C.M., V.D.F., A.D.C.), Istituto di Ricovero e Cura a Carattere Scientifico "Casa Sollievo della Sofferenza" General Hospital, San Giovanni Rotondo (Foggia); and the Department of Cell Biology and Oncology, Istituto di Ricerche Farmacologiche "Mario Negri," Consorzio Mario Negri Sud (D.C.), S. Maria Imbaro (Chieti), Italy

Address all correspondence and requests for reprints to: Dr. Alfredo Di Cerbo, Division of Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo (Foggia), Italy.

IgG associated with Graves’ disease bind to the TSH receptor and alter thyroid growth and function, mainly through the stimulation of adenylyl cyclase. In addition, Graves’ IgG are able to interact with the phospholipase C (PLC)/Ca²⁺ and phospholipase A₂ (PLA₂)/arachidonic acid (AA) cascades. The activation of this latter pathway leads to thyroid cell growth in vitro. The elucidation of additional mechanisms of action of Graves’ IgG has made possible the identification of four subgroups of patients, characterized by IgG with different biochemical activities (extent of cAMP and AA release stimulation in in vitro assays). On the basis of these results, a novel therapeutic approach could be proposed based on the inhibition of PLA₂ and AA metabolism.

To test this hypothesis, the ability of IgG from 56 Graves’ patients to stimulate [³H]thymidine incorporation in FRTL5 thyroid cells in the presence and absence of the cyclooxygenase inhibitor indomethacin (2.5 x 10^-6 mol/L) was measured. A significant reduction in [³H]thymidine incorporation was found (33% inhibition; P < 0.0001) upon pretreatment with indomethacin, suggesting that in vitro thyroid cell growth is regulated by cyclooxygenase metabolites. This strengthens the argument for involvement of the PLA₂/AA cascade in the pathophysiology of Graves’ disease and the proposal for novel selective pharmacological treatments of these patients.

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