Tumor necrosis factor (TNF) is known to play a role in several important inflammatory diseases. 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 sustained expression of genes encoding inflammatory molecules and 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 autocrine loop was dependant on interferon-response factor 1 (IRF1). “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.
MEDICA.de; Source: Hospital for Special Surgery