Long term interferon (IFN) therapy is frequently associated with side effects which affect the thyroid gland such as hypothyroidism and thyroiditis. We have therefore tested the ability of type I-IFNs to exert direct effects on primary cultures of human thyroid epithelial cells: (i) Type I-IFNs (IFN-alpha 2b and IFN-omega) inhibit cell proliferation as determined by [3H]thymidine incorporation with a half-maximal effect at approximately 1 ng/ml (50 pM). Inhibition of cell growth is observed in cells derived from normal thyroid as well as neoplastic tissue (autonomous and non-secreting adenoma; follicular, papillary and anaplastic carcinoma). (ii) Over a similar concentration range, type I-IFNs suppressed thyroglobulin release by thyroid cells. (iii) IFN-alpha 2b stimulated surface expression of major histocompatibility class (MHC) I but not MHC II molecules, while IFN-gamma enhanced the expression of both MHC I and MHC II molecules. This effect of IFN-gamma, but not that of IFN-alpha 2b was antagonized by suramin. (iv) Incubation of thyroid cells with IFN-alpha 2b also resulted in increased cell surface levels of the intercellular adhesion molecule 1 (ICAM-1). These findings demonstrate that type I-IFNs directly affect thyroid function and explain related side effects of these cytokines. In addition, our results provide a rational basis for the possible use of type I-IFNs in the treatment of patients with advanced thyroid cancer for whom no therapeutic alternative exists.