Novel Mechanism may Shed New Light on Inflammatory Diseases

Researchers at Hospital for Special Surgery have discovered a novel mechanism in the development of inflammatory diseases such as rheumatoid arthritis.

This mechanism, developed by Lionel Ivashkiv, M.D., director of Basic Research at Hospital for Special Surgery, may further shed some light on why gene therapy experiments involving adenoviruses for transferring genes to humans has faced problems.

It is known that Tumor necrosis factor (TNF) plays a pivotal role in a number of vital inflammatory diseases like rheumatoid arthritis. However, not much has been disclosed about early signalling pathways activated by TNF, and little is known about delayed and chronic TNF responses. Also, one knows that cells called macrophages produce TNF, but the effects of TNF on the macrophages themselves is still not clear.

In the current study, the scientists used human blood cells and mice, for assessing macrophages responses in the course of a two-day period after being stimulated with TNF. It was found that macrophages released TNF and after that the TNF activated surface receptors on the macrophages themselves, incited the cells into a low and sustained production of a protein called interferon-beta.

The resultant protein cooperated with TNF signals for not only inducing a sustained expression of genes encoding inflammatory molecules but also 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. It suggests a new mechanism by which TNF can drive and sustain inflammation,” Nature quoted Ivashkiv, as saying.

The scientist also revealed through experiments that the purported autocrine loop was dependant on the so-called interferon-response factor 1.

“This was the first implication that IRF1 was linked to TNF inflammatory pathways,” said Dr. Ivashkiv.

According to the researchers, the results of the studies may pave the way for finding new ways of preventing the bone destruction that linked with some diseases.

“There is the potential to control inflammation and also to control bone destruction. This interferon response is very effective at preventing the destruction of bones, which is one of the major issues with rheumatoid arthritis. So, what it does is sets up the next series of studies, in animal models, to try to determine whether this induction of interferon is beneficial or not,” said Dr. Ivashkiv.

The study may also help in explaining the death of a patient involved in a University of Pennsylvania gene therapy experiment that made use of an adenovirus to deliver the gene. Host response to adenoviral vectors is dependant on both IRF1 and TNF.

“What we have described is that TNF has both pathogenic affects—it helps to sustain some of these inflammatory chemokines, but it also has a potential protective effect, because some of these interferon responses limit the amount of cell proliferation and they can also help to limit inflammation.”

The study appeared in the recent online issue of the journal Nature Immunology.

Source-ANI
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