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Interleukin-4 Stimulates Papillary Thyroid Cancer Cell Survival: Implications in Patients with Thyroid Cancer and Concomitant Graves’ Disease

Istituto di Medicina Interna e di Malattie Endocrine e del Metabolismo (V.V., R.M., F.F., G.P., R.V.), Cattedra di Endocrinologia, University of Catania, Ospedale Garibaldi, 95123 Catania, Italy; Dipartimento di Biomorfologia e Biotecnologia (E.M.), University of Messina, Torre Biologica, Policlinico Universitario, 98122 Messina, Italy; and Dipartimento di Medicina Sperimentale e Clinica (A.B.), Cattedra di Endocrinologia, University of Catanzaro, Policlinico Mater Domini, 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Antonino Belfiore, M.D., Dipartimento di Medicina Sperimentale e Clinica, Cattedra di Endocrinologia, Università di Catanzaro, Policlinico Mater Domini, via Tommaso Campanella, 115-88100 Catanzaro, Italy. E-mail: belfiore{at}unicz.it.

IL-4, a pleiotropic cytokine mainly produced by activated helper T lymphocytes type 2 (Th2), is known to protect thyroid cells from autoimmune damage. Acting via its receptors (IL-4R), IL-4 has antiproliferative and apoptotic effects in many malignancies. Its effect in thyroid cancer is unknown.

We found that surgical specimens of thyroid carcinomas express both IL-4R and IL-4 in the majority of cases. Thyroid glands affected by Graves’ disease also express IL-4. We also studied a panel of eight thyroid cancer cell lines from different histotypes and found that thyroid cancer cells express high levels of IL-4R although they do not express IL-4.

We then compared the biological effects of IL-4 in TPC-1, a thyroid cancer cell line, and in MCF-7 breast cancer cells. IL-4 very weakly stimulated thyroid cancer cell proliferation, but it was very effective in protecting thyroid cancer cells from apoptosis induced by staurosporin. The protective effect of IL-4 was similar in magnitude to that of IGF-I and was associated with up-regulation of the antiapoptotic molecule Bcl-2 and weak down-regulation of the proapoptotic molecule Bax. Moreover, IL-4 slightly potentiated the survival effect of IGF-I. In contrast, IL-4 reduced growth and induced apoptosis in MCF-7 cells.

Taken together, these findings suggest that thyroid cancer cells receive significant protection from apoptosis by IL-4 produced in the thyroid gland by activated T lymphocytes when concomitant Graves’ disease is present.

This work was supported, in part, by the Associazione Italiana per la Ricerca sul Cancro (to A.B. and R.V.) and Ministero dell’Università e della Ricerca Scientifica e Tecnologica (Cofin 2003 to A.B.).

V.V. is the recipient of a fellowship from Fondazione Italiana per la Ricerca sul Cancro. F.F. is the recipient of a fellowship from the American Italian Cancer Foundation.

Abbreviations: CDK, Cyclin-dependent kinase; cFLIP, cellular FLICE-inhibitory protein; FBS, fetal bovine serum; IL-4R, IL-4 receptors; MTT, methyl thiazolyl tetrazolium; SDS, sodium dodecyl sulfate; TSAb, antibodies to the TSH receptor.

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