NEW YORK, NY—Tumor necrosis factor (TNF) triggers an autocrine loop in macrophages after 2 days of exposure that stimulate the cells into low and sustained production of interferon-β (IFN-β). These events then act synergistically with TNF to induce sustained expression of genes encoding inflammatory molecules and delaying expression of IFN-response genes. The latter normally primes macrophages to respond strongly to subsequent challenges with microbial products or cytokines. The loop is quite different from the previously identified TNF responses mediated by toll-like receptors, which involve “massive but rapid and transient” production of IFN-β.

The new signaling pathway was reported in the April issue of Nature Immunology by a research team led by Lionel B. Ivashkiv, director of basic research at the Hospital for Special Surgery in New York.1 Lead author was Anna Yarlina, MD, and other collaborators were Kyung-Hyun Park-Min, MD, Taras Antoniv, MD, and Xiaoyu Hu, MD. The study is the first to link interferon response factor-1 (IRF1) to TNF inflammatory pathways.

“There is the potential to control inflammation and to control bone destruction. This IFN response is effective at preventing the destruction of bones, which is one of the major issues with rheumatoid arthritis.”—Lionel B. Ivashkiv, MD.
“What we have described is that TNF has both pathogenic effects: it helps to sustain some of these inflammatory chemokines, and it also has a potential protective effect because some of these interferon responses limit the amount of cell proliferation, [which] can also help to limit inflammation,” Dr. Ivashkiv said.

The study grew out of efforts to understand the chronic or delayed effects of TNF on macrophages. Most TNF studies have involved only early responses, usually in fibroblasts or epithelial cells. The researchers investigated the kinetics of primary macrophage responses to TNF in cultured human peripheral blood mononuclear cells and in mice.

“The striking thing about many of these genes that came to our attention first was that there were these classic IFN response genes which had previously not been associated with TNF. It suggests a new mechanism by which TNF can drive and sustain inflammation,” Dr. Ivashkiv continued.

The investigators conclude that their “…findings describe a previously unknown signaling pathway induced by the well known cytokine TNF and provide evidence that the IRF–IFN-β–STAT1 pathway can be engaged by endogenous inflammatory factors such as TNF in addition to innate immune receptors that recognize microbial products.”

Translating research into practice

These findings also suggest new strategies for preventing inflammation-related bone destruction. “There is the potential to control inflammation and to control bone destruction. This IFN response is effective at preventing the destruction of bones, which is one of the major issues with rheumatoid arthritis,” Dr. Ivashkiv said.

Reference
1. Yarilina A, Park-Min K-H, Antoniv T, et al. TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes. Nat Immunol. [published online ahead of print March 16, 2008] 2008; doi:10.1038ni/XXXX. http://www.nature.com/ni/journal/v9/n4/abs/ni1576.html.