PMID- 9421427
OWN - NLM
STAT- MEDLINE
DCOM- 19980115
LR  - 20131121
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 139
IP  - 1
DP  - 1998 Jan
TI  - Regulation of major histocompatibility class II gene expression in FRTL-5 
      thyrocytes: opposite effects of interferon and methimazole.
PG  - 290-302
AB  - 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-gamma (IFNgamma). We have 
      studied IFNgamma-induced human leukocyte antigen (HLA)-DR alpha gene expression 
      in rat FRTL-5 thyroid cells to identify the elements and factors important for 
      aberrant expression. Using an HLA-DR alpha 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 
      IFNgamma can induce expression, and, as is the case for antigen-presenting cells 
      from the immune system, that IFNgamma-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 
      IFNgamma-induced increase in HLA-DR alpha gene expression as a function of time 
      and concentration; MMI simultaneously decreases IFNgamma-induced endogenous 
      antigen presentation by the cell. Using gel shift assays and the HLA-DR alpha 
      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 IFNgamma, termed the basal or constitutive complex, and 
      formation of an additional complex with a slightly faster mobility in extracts 
      from cells treated with IFNgamma. MMI treatment of cells prevents IFNgamma 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 IFNgamma-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 
      IFNgamma-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 IFNgamma, 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 
      IFNgamma and that do not express the class II gene.
FAU - Montani, V
AU  - Montani V
AD  - Metabolic Diseases Branch, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
FAU - Shong, M
AU  - Shong M
FAU - Taniguchi, S I
AU  - Taniguchi SI
FAU - Suzuki, K
AU  - Suzuki K
FAU - Giuliani, C
AU  - Giuliani C
FAU - Napolitano, G
AU  - Napolitano G
FAU - Saito, J
AU  - Saito J
FAU - Saji, M
AU  - Saji M
FAU - Fiorentino, B
AU  - Fiorentino B
FAU - Reimold, A M
AU  - Reimold AM
FAU - Singer, D S
AU  - Singer DS
FAU - Kohn, L D
AU  - Kohn LD
LA  - eng
GR  - KO8-AR-01915/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Antithyroid Agents)
RN  - 0 (HLA-DR Antigens)
RN  - 554Z48XN5E (Methimazole)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 9002-71-5 (Thyrotropin)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Animals
MH  - Antithyroid Agents/*pharmacology
MH  - Base Sequence
MH  - Cells, Cultured
MH  - DNA/metabolism
MH  - Gene Expression Regulation/*drug effects
MH  - *Genes, MHC Class II
MH  - HLA-DR Antigens/*genetics
MH  - Humans
MH  - Interferon-gamma/*pharmacology
MH  - Methimazole/*pharmacology
MH  - Mice
MH  - Molecular Sequence Data
MH  - Promoter Regions, Genetic
MH  - Rats
MH  - Thyroid Gland/cytology/*metabolism
MH  - Thyrotropin/pharmacology
EDAT- 1998/01/08 00:00
MHDA- 1998/01/08 00:01
CRDT- 1998/01/08 00:00
PHST- 1998/01/08 00:00 [pubmed]
PHST- 1998/01/08 00:01 [medline]
PHST- 1998/01/08 00:00 [entrez]
AID - 10.1210/endo.139.1.5658 [doi]
PST - ppublish
SO  - Endocrinology. 1998 Jan;139(1):290-302. doi: 10.1210/endo.139.1.5658.