Scientists reported on a new innate immune system-signaling pathway this week. Specifically targeting that pathway may make it possible to stop the tissue damage that cytokine signaling can cause without suppressing the immune system.

Cytokines are the innate immune system's rapid alert system. When macrophages sense an infection, they release cytokines, which activate, via the transcription factor NF-kappaB, gene expression programs that start up inflammatory cells to fight off the microbial invaders.

But, the University of Utah's Dean Li told BioWorld Today, what patients notice about the proinflammatory cytokines has nothing to do with that part of their response. Li is the senior author of the paper describing the new pathway, which was published in the Nov. 15, 2012, issue of Nature.

Cytokines, he elaborated, also affect cell-cell interactions, and in particular the cadherin molecules that hold the endothelial cells that line blood vessels together. And "the symptoms that most affect you with inflammation are a direct effect of cytokines on the vascular wall.

"When you sprain your ankle, you release cytokines. And the reason it gets swollen is that fluid is leaking out of your vessel wall," Li noted.

Sprained ankles will run their course without needing monoclonal antibodies. But the same basic mechanism contributes to inflammatory illnesses from rheumatoid arthritis to inflammatory bowel disease.

Current anti-inflammatory approaches, such as monoclonal antibodies Enbrel (etanercept, Amgen Inc.) and Humira (adalimumab, Abbott), target the first step of the problem, Li said. "We kill the cytokine."

But in doing so, the therapies are "blunting the good and bad effects" of those cytokines. And so, their biological price is suppression of the immune system.

Usually, that suppression does not lead to major problems. But in patients with latent infections it can make treatment impossible. For example, Li said, "in people with tuberculosis, it can lead to bad infections."

Li and his team have discovered, though, that cytokines effects on the vascular walls via a different signaling pathway than the NF-kappaB pathway is their best-known target. And that means it may be possible to keep cytokines from damaging blood vessels while still allowing them to activate the immune system.

Previous work had suggested to Li that cytokines might activate signals in addition to NF-kappaB, as did clinical observations. As a cardiologist, Li said he was aware of the fact that some people who are treated with steroids develop vascular leakage.

"The effect could not be through for transcription – it happens too fast. Those patients get into trouble within 15 minutes," while transcription-based effects take hours to kick in.

The pathway from cytokines to NF-kappaB runs via another molecule, myeloid-differentiating factor 88 (MyD88). And in the work now published in Nature, Li and his colleagues have shown that MyD88 also interacts with another signaling pathway, the ADP-ribosylation factor 6 (ARF6), and its activator, ARF nucleotide binding site opener, or ARNO. It is the ARNO signaling axis that affects vascular walls.

When the team treated animals with experimentally induced arthritis that was specific to inhibiting the ARF6/ARNO signaling pathway, they were able to improve their symptoms at a level that was comparable to treatment with Enbrel. Unlike Enbrel, however, their experimental inhibitor did not affect cytokine levels.

The work, Li said, suggests that developing small molecules that target the ARF-6 / ARNO branch of cytokine signaling while leaving NF-kappaB unaffected "might open up new possibilities [for anti-inflammatory drugs in indications] where immunosuppression was too steep a price to pay." One such example is TNF-alpha suppression, which has been tested for the treatment of heart failure. Li also pointed to the use of anti-interleukin-1beta antibodies that are currently in clinical trials to treat vascular disease, which he believes might run into similar problems.

Li is also a co-founder of biotech firm Navigen Pharmaceuticals Inc., which has licensed the patents on the findings from the University of Utah. Li said that for the work to meet its therapeutic potential, "a large company has to decide that this is a worthwhile approach, and then we can do a public-private partnership.

"We are interested in that," he said, "but this work is largely academic."