Tài liệu Báo cáo khoa học: Molecular aspects of rheumatoid arthritis: role of transcription factors

MINIREVIEW

Molecular aspects of rheumatoid arthritis: role of

transcription factors

Hiroshi Okamoto1

, Thomas P. Cujec2

, Hisashi Yamanaka1 and Naoyuki Kamatani1

1 Institute of Rheumatology, Tokyo Women’s Medical University, Japan

2 Ambrx, Inc. La Jolla, CA, USA

The central dogma of molecular biology is that DNA

produces RNA, which, in turn, produces protein. In

the process of transcription, RNA is produced from

the DNA and this conversion is an essential element in

gene expression. The central role of transcription in

the process of gene expression makes it an attractive

control process for regulating the expression of genes

in particular cell types or in response to a particular

signal, such as a cytokine. To study this control mech￾anism, the DNA sequences within individual genes

that are essential for basal or regulated gene expression

have been extensively studied. In most eukaryotic

genes a TATA box is found upstream of the site of

transcriptional initiation, although this element is lack￾ing in housekeeping genes and in some tissue-specific

genes. In the genes without a TATA box, a sequence

known as the initiator element, which is located over

the start site of transcription, appears to play a critical

role in determining the initiation point and acts as a

minimal promoter capable of producing basal levels of

transcription. In TATA-less promoters, the weak acti￾vity of the promoter is dramatically increased by other

elements located upstream of the proximal promoter

region. These elements are found in a wide variety of

Keywords

NFAT; NF-jB; rheumatoid arthritis;

transcription factors

Correspondence

H. Okamoto, Institute of Rheumatology,

Tokyo Women’s Medical University, 10-22

Kawada-cho, Shinjuku, Tokyo 162-0054,

Japan

Fax: +81 3 5269 1726

Tel: +81 3 5269 1725

E-mail: [email protected]

(Received 14 March 2008, accepted 22 May

2008)

doi:10.1111/j.1742-4658.2008.06582.x

Rheumatoid arthritis is a multifactorial disease characterized by chronic

inflammation of the joints. Both genetic and environmental factors are

involved in the pathogenesis leading to joint destruction and ultimately dis￾ability. In the inflamed RA joint the synovium is highly infiltrated by

CD4+ T cells, B cells and macrophages, and the intimal lining becomes

hyperplastic owing to the increased number of macrophage-like and fibro￾blast-like synoviocytes. This hyperplastic intimal synovial lining forms an

aggressive front, called pannus, which invades cartilage and bone struc￾tures, leading to the destruction and compromised function of affected

joints. This process is mediated by a number of cytokines (tumor

necrosis factor-a, interleukin-1, interleukin-6, interleukin-17 interferon-c,

etc.), chemokines (monocyte chemoattractant protein-1, monocyte chemo￾attractant protein-4 CCL18, etc.), cell adhesion molecules (intercellular

adhesion molecule-1, vascular cell adhesion molecule-1, etc.) and matrix

metalloproteinases. Expression of these molecules is controlled at the tran￾scription level and activation of a limited number of transcription factors is

involved in this process.

Abbreviations

AGE, advanced glycation end-product; AP-1, activator protein-1; FLIP, Fas-associated death domain-like interleukin 1b-converting enzyme￾inhibitory protein; FLS, fibroblast-like synoviocytes; GM-CSF, granulocyte–macrophage colony-stimulating factor; IKK, IjB kinase; IL,

interleukin; IjB, inhibitor of NF-jB proteins; MMP, matrix metalloproteinase; NFAT, nuclear factor for activation of T cells; NF-jB, nuclear

factor-jB; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; RA, rheumatoid arthritis;

RAGE, receptor for advanced glycation end-products; RANKL, receptor activation of NF-jB ligand; SAA, serum amyloid A; TNF-a, tumor

necrosis factor-a.

FEBS Journal 275 (2008) 4463–4470 ª 2008 The Authors Journal compilation ª 2008 FEBS 4463