Scientists shine new light on inflammatory diseases

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.

The researchers say that these findings could lead scientists to ways of preventing the bone destruction that is associated 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,” said Dr. Ivashkiv. “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.”

The new research could also help explain how a patient involved in a University of Pennsylvania gene therapy experiment that used an adenovirus to deliver the gene died. 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.”

Source: Hospital for Special Surgery

Explore further: Second bird flu case confirmed in Canada

add to favorites email to friend print save as pdf

Related Stories

Nanodiamond coatings safe for implants: study

Feb 05, 2012

Nanodiamonds designed to toughen artificial joints also might prevent the inflammation caused when hardworking metal joints shed debris into the body, according to an early study published this week in the ...

Recommended for you

Ebola reveals shortcomings of African solidarity

11 hours ago

As Africa's leaders meet in Ethiopia to discuss the Ebola crisis, expectations of firm action will be tempered by criticism over the continent's poor record in the early stages of the epidemic.

Second bird flu case confirmed in Canada

Jan 30, 2015

The husband of a Canadian who was diagnosed earlier this week with bird flu after returning from a trip to China has also tested positive for the virus, health officials said Friday.

What exactly is coronavirus?

Jan 30, 2015

The conflicts in Syria and Iraq are straining public health systems and public health efforts meant to prevent and detect the spread of infectious diseases. This is generating a "perfect storm" of conditions for outbreaks. Among the infections raising concern is Middle East Respiratory Syndrome, caused by a type of coronavirus, which emerged in 2012. ...

Scientists find Ebola virus is mutating

Jan 30, 2015

(Medical Xpress)—Researchers working at Institut Pasteur in France have found that the Ebola virus is mutating "a lot" causing concern in the African countries where the virus has killed over eight thous ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.