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J. Biol. Chem., Vol. 279, Issue 40, 41319-41332, October 1, 2004
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Major Histocompatibility Class II Transactivator (CIITA) Mediates Repression of Collagen (COL1A2) Transcription by Interferon 
(IFN-)*
From the Department of Biochemistry, Boston University School of Medicine and the Veterans Administration Boston Healthcare System, Boston, Massachusetts 02118
Interferon 
(IFN-) plays an important role during inflammation by repressing collagen and activating major histocompatibility class II (MHC-II) expression. Activation of MHC-II by IFN- requires regulatory factor for X-box 5 (RFX5) complex as well as class II transactivator (CIITA). We have shown that the RFX family binds to the COL1A2 transcription start site (Sengupta, P. K., Fargo, J., and Smith, B. D. (2002) J. Biol. Chem. 277, 24926–24937), and the RFX5 complex represses COL1A2 gene expression during IFN- response (Xu, Y., Wang, L., Buttice, G., Sengupta, P. K., and Smith, B. D. (2003) J. Biol. Chem. 278, 49134–49144). In this report, we demonstrate that CIITA is a key mediator of COL1A2 repression by IFN-. IFN- up-regulates the expression of CIITA in a time-dependent manner in lung fibroblasts and promotes CIITA protein occupancy on COL1A2 transcription start site in vivo as judged by chromatin immunoprecipitation (ChIP) assays. There are coordinate decreases in the occupancy of RNA polymerase II on the collagen transcription start site with increasing CIITA occupancy during IFN- treatment. In addition, we are able to specifically knockdown the IFN--stimulated expression of CIITA utilizing short hairpin interference RNA (shRNA) against CIITA. This leads to the alleviation of COL1A2 repression and MHC-II activation by IFN-. RFX5 recruits CIITA to the collagen site as evidenced by DNA affinity chromatography. The presence of RFX5 complex proteins enhances the collagen repression by CIITA reaching levels occurring during IFN- treatment. Co-expression of CIITA with deletion mutations and collagen promoter constructs demonstrates that CIITA represses collagen promoter mainly through its N-terminal region including the acidic domain and the proline/serine/threonine domain. Our data suggest that CIITA is a crucial member of a repressor complex responsible for mediating COL1A2 transcription repression by IFN-.
Received for publication, April 14, 2004 , and in revised form, June 30, 2004.
* This work was funded in part by a Veterans Administration merit review project and by NHLBI, National Institutes of Health Grants R01-HL68094 and P01-HL013262–31. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains three figures in Supplemental Materials.
To whom correspondence should be addressed: Dept. of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4159; Fax: 617-638-5339; E-mail: smith{at}biochem.bumc.bu.edu.
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