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

J Clin Endocrinol Metab. 2004 Jun;89(6):2880-9. doi: 10.1210/jc.2003-031639.


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-4Ralpha), 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-4Ralpha 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-4Ralpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms
  • Carcinoma, Papillary / complications*
  • Carcinoma, Papillary / pathology
  • Carcinoma, Papillary / physiopathology
  • Cell Division / drug effects
  • Cell Line, Tumor / cytology
  • Cell Line, Tumor / drug effects
  • Cell Survival / drug effects
  • Gene Expression Regulation, Neoplastic
  • Graves Disease / etiology*
  • Graves Disease / physiopathology
  • Humans
  • Interleukin-4 / genetics
  • Interleukin-4 / pharmacology*
  • Neoplasm Invasiveness
  • Receptors, Interleukin-4 / genetics
  • Th2 Cells / metabolism
  • Thyroid Neoplasms / complications*
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / physiopathology


  • Receptors, Interleukin-4
  • Interleukin-4