Cytokines are important modulators of immunological reactions, but it has been postulated that they might act on other unrelated epithelial cells. We studied the effects of recombinant interferon-γ (rIFNγ) and recombinant tumor necrosis factor-α (rTNFα) on normal human thyroid cells. We found that the combination of these two cytokines enhanced HLA class II molecule expression on these cells compared with the effect of rIFNγ alone. This was proven by both immunofluorescence as well as a more sensitive and quantitative RIA. rTNFα alone had no effect on HLA class II molecule induction on the same thyrocytes, suggesting a synergistic rather than an additive action in combination with rIFNγ. The addition of 600 U/ml rTNFα to low dose rIFNγ (10 U/mL) enhanced class II expression by 50%, as quantified by RIA. We also demonstrated that normal thyrocytes possess distinct receptors for the two cytokines and that rTNFα probably augments IFNγ binding, since it increased when the cells were first incubated with rTNFα. This increased binding provides an explanation for the synergistic action of rTNFα in enhancing class II molecule expression by rlFNγ. We conclude that the presence of receptors for these cytokines on human thyroid cells gives a direct demonstration of their potential biological action on cells normally not involved in the immunological circuit. The phenomenon might also explain their direct or indirect involvement in vivo, such as in influencing inappropriate HLA class II molecule expression in epithelial cells affected by autoimmunity. © 1989 by The Endocrine Society.