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Scientists shine new light on inflammatory diseases
Date:3/16/2008

NEW YORK CITY, Mar. 16, 2008--Investigators at Hospital for Special Surgery have identified a new mechanism involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis. The mechanism may also shed some light on why gene therapy experiments that use adenoviruses to deliver genes to humans have run into problems. The study will appear online on March 16 in the journal Nature Immunology.

Tumor necrosis factor (TNF) is known to play a role in several important inflammatory diseases including rheumatoid arthritis. While much is known about early signaling pathways activated by TNF, little is known about delayed and chronic TNF responses. In addition, cells called macrophages produce TNF, but little is known about the effects of TNF on the macrophages themselves.

In studies using human blood cells and mice, scientists examined the responses of macrophages during a two-day period after being stimulated with TNF. They found that macrophages secreted TNF and that then the TNF activated surface receptors on the macrophages themselves, spurring the cells into a low and sustained production of a protein called interferon-beta. This protein acted synergistically with TNF signals to induce 1) sustained expression of genes encoding inflammatory molecules and 2) delayed expression of genes encoding interferon-response molecules.

The striking thing about many of these genes that came to our attention first was that there were these classic interferon response genes which had previously not been associated with TNF, said Lionel Ivashkiv, M.D., director of Basic Research at Hospital for Special Surgery, who led the study. It suggests a new mechanism by which TNF can drive and sustain inflammation.

Experiments also revealed that the so-called autocrine loop was dependant on so-called interferon-response factor 1. This was the first implication that IRF1 was linked to TNF inflammatory pathways, said Dr. Ivashkiv.

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Contact: Phyllis Fisher
fisherp@hss.edu
212-606-1197
Hospital for Special Surgery
Source:Eurekalert

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