Researchers led by scientists at the University of California, San Diego School of Medicine say they have discovered new links between inflammation and regeneration, i.e., signaling pathways that are activated by the gp130 receptor protein.

“gp130 is capable of activating several signaling pathways that turn on a number of transcription factors known to have a key role in stem cell biology,” said Koji Taniguchi, M.D., Ph.D. Dr. Taniguchi is assistant project scientist in the department of pharmacology at UC San Diego and lead author of the study (“A gp130–Src–YAP module links inflammation to epithelial regeneration”), which is published in Nature.

“This signalling module [gp130] is strongly activated upon mucosal injury to promote healing and maintain barrier function,” wrote the investigators.

The STAT3, YAP, and Notch transcription factors stimulate the proliferation and survival of normal tissue stem cells, which lead to healing and repair, said senior author Michael Karin, Ph.D., distinguished professor pharmacology and pathology and head of UC San Diego's laboratory of gene regulation and signal transduction.

“While the work was mainly conducted on a mouse model of intestinal injury, similar to the one that underlies human inflammatory bowel disease (IBD), we provide evidence that the same mechanism may control liver regeneration, which suggests a general role in tissue repair,” continued Dr. Karin.

In addition to explaining a key biomedical phenomenon, the researchers believe their findings have important clinical implications for the treatment of IBD and colorectal cancer. The major signal sensed by gp130 is the IL-6 cytokine and closely related proteins. Expression of IL-6 has been found to be elevated in IBD, both in Crohn's disease and ulcerative colitis, giving rise to the possibility that inhibition of IL-6 binding to its receptor (a complex between gp130 and a specific IL-6 binding protein) may ameliorate the pathology of IBD.

But just the opposite has been observed. Drugs that block the binding of IL-6 to its receptor complex actually increase the risk of intestinal perforation and bleeding, making them unsuitable for the treatment of IBD. The new work suggests that IL-6 and the signaling pathways it stimulates are not the cause of IBD, but are part of the natural protective reaction to the initial injury and inflammatory response associated with the onset of IBD.

The Taniguchi and Karin team say it is important that future treatments not interfere with the healing response triggered by IL-6 and gp130. Nonetheless, the same pathways involved in healing and regeneration can go awry and become chronically stimulated in colorectal cancer.

The new work defines several molecular targets suitable for development of new targeted therapies for this very common malignancy though Dr. Karin cautioned that “such treatments should not be combined with conventional and highly toxic anti-cancer drugs whose major side effect is damage and inflammation of the intestinal mucosa, a disease known as mucositis that will only be exacerbated by blocking the regenerative response triggered by IL-6.”








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