Isoforms of the class II transactivator protein

Barbieri, Giovanna; Deffrennes, Virginie; Prod’homme, Thomas; Vedrenne, Jocelyn; Baton, Fabrice; Cortés, Claudio; Fischer, Alain; Bono, Maria-Rosa; Lisowska-Grospierre, B; Charron, Dominique; Alcaïde‐Loridan, Catherine

doi:10.1093/intimm/dxf060

Cited by 14 publications

(14 citation statements)

References 48 publications

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“…In some experiments, CIITA protein was detectable at 2 hours and the level was reduced at 24 hours, peaking between 6 and 24 hours, similar to other cells. 28,29 RFX5, a DNA-binding protein that recruits CIITA, is constitutively expressed and induced (3-fold) with time by IFN-␥ in aortic SMCs (supplemental Figure II). These results show that SMCs produce a significant amount of IFN-␥ inducible CIITA and RFX-5 and that CIITA types III and IV are the foremost isoforms present in this cell type.…”

Section: Human Aortic Smcs Express Two Ciita Isoforms That Are Highlymentioning

confidence: 99%

Interferon-γ Induces Major Histocompatibility Class II Transactivator (CIITA), Which Mediates Collagen Repression and Major Histocompatibility Class II Activation by Human Aortic Smooth Muscle Cells

Butticè

Miller

Wang

et al. 2006

Circulation Research

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Abstract-Chronic inflammation in atherosclerosis is responsible for plaque instability through alterations in extracellular matrix. Previously, we demonstrated that major histocompatibility class II (MHC II) transactivator (CIITA) in a complex with regulatory factor for X box 5 (RFX5) is a crucial protein mediating interferon (IFN)-␥-induced repression of collagen type I gene transcription in fibroblasts. This article demonstrates that, in smooth muscle cells (SMCs), IFN-␥ dramatically increases the expression of CIITA isoforms III and IV, with no increase in expression of CIITA isoform I. Expression of CIITA III and IV correlates with decreased collagen type I and increased MHC II gene expression. Exogenous expression of CIITA I, III, and IV, in transiently transfected SMCs, represses collagen type I promoters (COL1A1 and COL1A2) and activates MHC II promoter. Levels of CIITA and RFX5 increase in the nucleus of cells treated with IFN-␥. Moreover, simvastatin lowers the IFN-␥-induced expression of RFX5 and MHC II in addition to repressing collagen expression. However, simvastatin does not block the IFN-␥-induced expression of CIITA III and IV, suggesting a CIITA-independent mechanism. This first demonstration that RFX5 and CIITA isoforms are expressed in SMCs after IFN-␥ stimulation suggest that CIITA could be a key factor in plaque stability in atherosclerosis. Key Words: collagen Ⅲ CIITA isoform Ⅲ RFX Ⅲ MHC II Ⅲ SMCs A therosclerosis is a complex inflammatory and fibroproliferative process in which the immune system 1-3 and the extracellular matrix environment 4 play an important role in the pathogenesis of disease. Initially, atherosclerotic lesions consist of fatty streaks that can develop into mature lesions containing macrophages, T lymphocytes, smooth muscle cells (SMCs), a necrotic core, and a fibrous cap containing extracellular matrix components. Clinical complications of atherosclerosis arise when plaques rupture. Instability of the atherosclerotic plaques is a result of an unbalanced synthesis and degradation of extracellular matrix components including collagens. 5 Collagen type I, composed of 2 proteins, ␣1(I) and ␣2(I), transcribed by 2 separate genes, COL1A1 and COL1A2, is the most abundant fibrillar protein secreted by SMCs in atherosclerotic lesions 6 and by SMCs in culture. 7 A lower content of collagen has been observed in atherosclerotic lesions that are prone to rupture. 8 However, the mechanism by which the collagen content decreases in plaques has not been fully elucidated.Chronic inflammation in atherosclerosis is accompanied by secretion of cytokines, a major one being the interferon (IFN)-␥, which is secreted by T lymphocytes and macrophages. 9,10 IFN-␥ decreases collagen gene expression and activates major histocompatibility class II (MHC II) gene transcription through similar transcription regulatory proteins, RFX5 and CIITA, in fibroblast cells. [11][12][13] However, little is known about the expression and the mechanism of regulation of collagen and MHC II genes by IFN-␥ in SMC...

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Section: Human Aortic Smcs Express Two Ciita Isoforms That Are Highlymentioning

confidence: 99%

Interferon-γ Induces Major Histocompatibility Class II Transactivator (CIITA), Which Mediates Collagen Repression and Major Histocompatibility Class II Activation by Human Aortic Smooth Muscle Cells

Butticè

Miller

Wang

et al. 2006

Circulation Research

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“…These experiments were performed in the HeLa cell line in which we have shown that recombinant CIITA is expressed at levels close to physiological ones. 16 Functional complementation of this cell line is therefore useful as it allows to discriminate fully invalidating defects from leaky mutations. 48 We additionally have examined the level of CIITA protein expression in the transfected clones without evidencing any reduction when compared to cell clones transfected with the wild-type cDNA (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…As previously reported by our group, CIITA is expressed in the Raji cell line as two isoforms, B-CIITA and F-CIITA, where B-CIITA is 24 amino acids longer in its N-terminal extremity due to an alternative usage of translation initiation codons. 16 The RJ2.2.5 cell line presents defects in both alleles of MHC2TA.…”

Section: Ciita Protein Expression Is Strongly Reduced In the Rec-1 Cementioning

confidence: 99%

“…14,15 This tissue-specific usage of promoters leads to the generation of three isoforms of CIITA differing in their amino-terminal extremities. 16,17 MHC class II deficiency is a hereditary disease leading to a severe immunodeficiency, currently named the bare lymphocyte syndrome (BLS). 18 Genetic complementation analysis carried out with patient-derived BLS cell lines has defined four complementation groups (groups A-D).…”

Section: Introductionmentioning

confidence: 99%

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Defective class II transactivator expression in a B lymphoma cell line

et al. 2004

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Loss of MHC class II expression in B-cell lymphoma has been associated with a higher tumorigenicity resulting from lower titers of tumor-infiltrating lymphocytes. This report aims towards the identification of the molecular mechanism leading to defective MHC class II expression in a B-cell lymphoma cell line, Rec-1. We evidenced a coordinated alteration of HLA-D gene transcription, reminiscent of B lymphoblastoid cell lines from patients with MHC class II deficiency. Genetic complementation performed between these cell lines and the lymphoma cells indicated that Rec-1 is altered in the MHC2TA gene. MHC2TA encodes the class II transactivator (CIITA), the master regulator of HLA-D gene expression. However, the coding sequence of the Rec-1 CIITA transcript did not reveal any mutation that could hamper the activity of the encoded protein.In agreement with the genetic complementation analysis, we evidenced a highly residual CIITA protein expression in the Rec-1 cell line resulting from a transcriptional defect affecting MHC2TA expression. Anti-HLA-DR monoclonal antibody treatment has proved efficient in the destruction of B lymphoma cells. Our data indicate that the appearance of variants losing CIITA, and thereby HLA-DR, expression will require a thorough monitoring during such immunotherapy protocols.

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“…17,18,31,32 In Ovx-B6 mice, significant CIITA mRNA expression in the salivary and lacrimal gland tissues was observed respectively at 2 weeks and 3 weeks after ovariectomy, and later declined with age by quantitative RT-PCR analysis ( Figure 1C). CIITA has three different isoforms synthesized from different, cellspecific promoters 33 ; promoter I is mainly used in dendritic cells, promoter III in B lymphocytes, and promoter IV in nonhematopoietic cells. The CIITA expression was controlled by each promoter referred to as type I, III, and IV.…”

Section: Tissue-specific Mhc Class II Expressions In the Exocrine Glamentioning

confidence: 99%

Role of Plasmacytoid Dendritic Cells for Aberrant Class II Expression in Exocrine Glands from Estrogen-Deficient Mice of Healthy Background

Arakaki

Nagaoka

Ishimaru

et al. 2009

The American Journal of Pathology

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Although it has been well documented that aberrant major histocompatibility complex class II molecules may contribute to the development of autoimmune disorders, the precise mechanisms responsible for their tissue-specific expression remain unknown. Here we show that estrogen deficiency induces aberrant class II major histocompatibility complex expression in exocrine glands via interactions between epithelial cells and plasmacytoid dendritic cells. Relatively modest but functionally significant expression levels of major histocompatibility complex class II and class II transactivator molecules were observed in the exocrine glands of ovariectomized (Ovx) C57BL/6 (B6) mice, but were not seen in the exocrine glands of control B6 mice. We observed that the salivary dendritic cells adjacent to the apoptotic epithelial cells positive for terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling, were activated in Ovx mice, but were not activated in control mice. We obtained evidence that the salivary gland cells express both interferon regulatory factor-1 and class II transactivator type IV molecules in Ovx mice. Major histocompatibility complex (MHC) class II molecules are crucial for restricting immune reactivity to self versus foreign antigens during thymic education, and their expression level is essential for determining T cell activation in the periphery.1-3 MHC class II molecules are basically expressed on antigen (Ag)-presenting cells of the hematopoietic lineage, but can be induced by unknown stimuli on many other cell types (such as endothelial cells, hepatocytes, pancreatic ␤-cells, thyrocytes, and salivary gland cells) in association with autoimmunity.4 -10 MHC class II proteins play a central role in the control of normal immune homeostasis, while aberrant expression of MHC class II is frequently associated with abnormalities in immune responses.11-13 MHC class II expression is regulated by multiple cytokines, including interferon (IFN)-␥, which can enhance the immune response by upregulating MHC class II expression in immune cells, in addition to inducing Ag-presentation capacity.14,15 It is well known that the induction of MHC class II gene transcription by IFN-␥ is mediated by the MHC class II transactivator (CIITA), and depends on the presence of two transcription factors; signal transducer and activator of transcription 1 and interferon regulatory factor (IRF-1). 16 CIITA is a true co-activator because it does not bind directly to DNA but mediates its function on the class II MHC promoter through interaction with other proteins. 17,18 It is considered a master regulator because it is necessary and sufficient for the expression of all of the genes in the MHC class II pathway. Although recent studies have begun to reveal that epigenetic mechanisms have a key role in activating CIITA expression in normal cells, 19 the factors regulating this promoter have yet to be investigated.

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Isoforms of the class II transactivator protein

Cited by 14 publications

References 48 publications

Interferon-γ Induces Major Histocompatibility Class II Transactivator (CIITA), Which Mediates Collagen Repression and Major Histocompatibility Class II Activation by Human Aortic Smooth Muscle Cells

Interferon-γ Induces Major Histocompatibility Class II Transactivator (CIITA), Which Mediates Collagen Repression and Major Histocompatibility Class II Activation by Human Aortic Smooth Muscle Cells

Defective class II transactivator expression in a B lymphoma cell line

Role of Plasmacytoid Dendritic Cells for Aberrant Class II Expression in Exocrine Glands from Estrogen-Deficient Mice of Healthy Background

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