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zoom RSS マクロファージの活動を制御するスイッチとなる蛋白

<<   作成日時 : 2011/01/22 19:29   >>

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画像 白血球が炎症を強めたり弱めたりするための「マスタスイッチ」として作動する蛋白質を見つけたという。
 関節リウマチの多くの患者は腫瘍壊死因子(TNF)阻害剤として知られている薬剤により治療されるが、約30%の患者はこの薬剤に反応しないため、より効果的な治療オプションを至急開発する必要がある。
 マクロファージが炎症を促進したり抑制したりするスイッチとなるタンパク質IRF5 をImperial College in London の科学者が発見した。
 IRF5の生産を阻害することで自己免疫疾患の効果的な治療に役立つ可能性がある。逆にIRF5レベルを増加させれば免疫不全の治療に役立つ可能性がある。

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Scientists find inflammation immune cell switch
http://www.reuters.com/article/idUSTRE70F1XS20110116

By Kate Kelland

LONDON | Sun Jan 16, 2011 1:03pm EST

LONDON (Reuters) - Scientists have found a protein that acts as a "master switch" to determine whether certain white blood cells will boost or dampen inflammation, a finding that may help the search for new drugs for rheumatoid arthritis.

Many patients with rheumatoid arthritis are treated with a class of drugs known as tumor necrosis factor (TNF) inhibitors made by various drug firms including Abbott Laboratories, Merck & Co, Pfizer and Amgen

But around 30 percent of patients don't respond to anti-TNF drugs, so experts say there is an urgent need to develop more widely effective treatment options.

In this study, scientists from Imperial College in London found that a protein called IRF5 acts as a molecular switch that controls whether certain white blood cells, known as macrophages, will promote or inhibit inflammation.

In a report of their findings in the journal Nature Immunology on Sunday, they said the results suggest that blocking the production of IRF5 in macrophages might be an effective way of treating a wide range of autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, lupus and multiple sclerosis.

They also suggest that boosting IRF5 levels might help treat people whose immune systems are weak, compromised or damaged.

"Our results show that IRF5 is the master switch in a key set of immune cells, which determines the profile of genes that get turned on in those cells," Irina Udalova, senior researcher on the study, said in a statement.

"This is really exciting because it means that if we can design molecules that interfere with IRF5 function, it could give us new anti-inflammatory treatments for a wide variety of conditions."

The researchers said IRF5 seems to work by switching on genes that stimulate inflammatory responses and dampening genes that inhibit them.

It can do this either by interacting with DNA directly, or by interacting with other proteins that themselves control which genes are switched on, they explained in their study.

Udalova's team is now studying how IRF5 works at a molecular level and which other proteins it interacts with so that they can design ways to block its effects.

Rheumatoid arthritis is a chronic inflammatory disease affecting around 1 percent of the world's population and arises when the immune system mistakenly attacks joints all over the body. As well as joints, it may also affect the skin, heart, lungs, kidneys and blood vessels. Many sufferers get deformed hands and feet, which hamper movement and ability to function.

(Editing by David Holmes)

-----------------------------------------------------
IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses

* Thomas Krausgruber,
* Katrina Blazek,
* Tim Smallie,
* Saba Alzabin,
* Helen Lockstone,
* Natasha Sahgal,
* Tracy Hussell,
* Marc Feldmann
* & Irina A Udalova

Nature Immunology
Year published: (2011) DOI: doi:10.1038/ni.1990
Received 02 November 2010
Accepted 20 December 2010
Published online 16 January 2011

Abstract

Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (TH1)-TH17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.

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