IODIDE SUPPRESSION OF MAJOR HISTOCOMPATIBILITY CLASS-I GENE-EXPRESSION IN THYROID-CELLS INVOLVES ENHANCER-A AND THE TRANSCRIPTION FACTOR NF-KAPPA-B

High concentrations of iodide can induce transient, clinical improveme nt in patients with autoimmune Graves' disease. Previous work has rela ted this iodide action to the autoregulatory effect of iodide on the g rowth and function of the thyroid; more recently, we additionally rela ted this to the ability of iodide to suppress major histocompatibility (MHC) class I RNA levels and antigen expression on thyrocytes. In thi s report, we describe a transcriptional mechanism involved in iodide s uppression of class I gene expression, which is potentially relevant t o the autoregulatory action of iodide. Transfection experiments in FRT L-5 cells show that iodide decreases class I promoter activity and tha t this effect can be ascribed to the ability of iodide to modulate the formation of two specific protein/DNA complexes with enhancer A, -180 to -170 bp, of the class 1 5'-flanking region.(1) Thus, iodide decrea ses the formation of Mod-1, an enhancer A complex involving the p50 su bunit of NF-kappa B and a c-fos family member, fra-2, which was previo usly shown to be important in the suppression of class I levels by hyd rocortisone. Unlike hydrocortisone, iodide also increases the formatio n of a complex with enhancer A, which we show, in antibody shift exper iments, is a heterodimer of the p50 and p65 subunits of NF-kappa B. Th e changes in these complexes are not duplicated by chloride and are re lated to the action of iodide on class I RNA levels by the following o bservations. First, FRTL-5 thyroid cells with an aged phenotype coinci dentally lose the ability of iodide to decrease MHC class I RNA levels and to induce changes in either complex. Second, the effect of iodide on class I RNA levels and on enhancer A complex formation with Mod-1 and the p50/p65 heterodimer is inhibited by agents that block the inos itol phosphate, Ca++, phospholipase A2, arachidonate signal transducti on pathway: acetylsalicylate, indomethacin, and 5,8,11,14-eicosatetray noic acid. Interestingly, iodide can also decrease formation of the Mo d-1 complex and increase formation of the complex with the p50/p65 sub units of NF-kappa B when the NF-kappa B enhancer sequence from the Ig kappa light chain, rather than enhancer A, is used as probe; and both actions mimic the action of a phorbol ester. This suggests that iodide may regulate complex formation with NF-kappa B regulatory elements on multiple genes associated with growth and function, providing a poten tial mechanism relating the autoregulatory action of iodide on thyroid cells and its action on class I gene expression.