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Cell Regulation Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (M.S., S.-i.T., K.S., C.G., G.N., J.S., M.S., B.F., L.D.K.), and Experimental Immunology Branch, National Cancer Institute (D.S.S.), National Institutes of Health, Bethesda, Maryland 20892; the Department of Surgery, Johns Hopkins University (M.S.), Baltimore, Maryland 21287; and the Departments of Cancer Biology and Medicine, Harvard School of Public Health and Harvard Medical School (A.M.R.), Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Dr. Leonard D. Kohn, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 9C101B, National Institutes of Health, Bethesda, Maryland 20892-1360. E-mail: lenk{at}bdg10.niddk.nih.gov
Aberrant expression of major histocompatibility complex (MHC) class II
antigens is associated with autoimmune thyroid disease; aberrant
expression duplicating the autoimmune state can be induced by
interferon-
(IFN). We have studied IFN-induced human leukocyte
antigen (HLA)-DR
gene expression in rat FRTL-5 thyroid cells to
identify the elements and factors important for aberrant expression.
Using an HLA-DR 5'-flanking region construct from -176 to +45 bp
coupled to the chloramphenicol acetyltransferase reporter gene, we show
that there is no basal class II gene expression in FRTL-5 thyroid
cells, that IFN can induce expression, and, as is the case for
antigen-presenting cells from the immune system, that IFN-induced
expression requires several highly conserved elements on the
5'-flanking region, which, from 5' to 3', are the S, X1,
X2, and Y boxes. Methimazole (MMI), a drug used to treat
patients with Graves’ disease and experimental thyroiditis in rats or
mice, can suppress the IFN-induced increase in HLA-DR gene
expression as a function of time and concentration; MMI simultaneously
decreases IFN-induced endogenous antigen presentation by the cell.
Using gel shift assays and the HLA-DR 5'-flanking region from -176
or -137 to +45 bp as radiolabeled probes, we observed the formation of
a major protein-DNA complex with extracts from FRTL-5 cells untreated
with IFN, termed the basal or constitutive complex, and formation of
an additional complex with a slightly faster mobility in extracts from
cells treated with IFN. MMI treatment of cells prevents IFN from
increasing the formation of this faster migrating complex. Formation of
both complexes is specific, as evidenced in competition studies with
unlabeled fragments between -137 and -38 bp from the start of
transcription; nevertheless, they can be distinguished in such studies.
Thus, high concentrations of double stranded oligonucleotides
containing the sequence of the Y box, but not S, X1, or
X2 box sequences, can prevent formation of the
IFN-increased faster migrating complex, but not the basal complex.
Both complexes involve multiple proteins and can be distinguished by
differences in their protein composition. Thus, using specific
antisera, we show that two cAMP response element-binding proteins,
activating transcription factor-1 and/or -2, are dominant proteins in
the upper or basal complex. The upper or basal complex also includes
c-Fos, Fra-2, Ets-2, and Oct-1. A dominant protein that distinguishes
the IFN-increased lower complex is CREB-binding protein (CBP), a
coactivator of cAMP response element-binding proteins. We, therefore,
show that aberrant expression of MHC class II in thyrocytes, induced by
IFN, is associated with the induction or increased formation of a
novel protein-DNA complex and that its formation as well as aberrant
class II expression are suppressed by MMI, a drug used to treat human
and experimental autoimmune thyroid disease. Its component proteins
differ from those in a major, basal, or constitutive protein-DNA
complex formed with the class II 5'-flanking region in cells that are
not treated with IFN and that do not express the class II gene.
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