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Protein finding could lead to treatment for inflammatory diseases

A protein that undesirably shields a skin poxvirus from the immune system may become the key ingredient in a new topical treatment for inflammatory diseases, say medical researchers at the University of Illinois at Urbana-Champaign.

In a study appearing this month in the Journal of Virology, the scientists revealed both the function of the protein (MC160) and how it works on a molecular level to inhibit inflammatory responses.

MC160 is so named because it was the 160th gene of the molluscum contagiosum virus (MCV) sequence. "This is a really important protein for a couple of reasons," said Joanna L. Shisler, a professor of microbiology in the U. of I. College of Medicine at Urbana-Champaign who studies poxviruses.

"MC160 first piqued our curiosity because it has a homologue in humans and in herpes viruses, and each of these homologues regulate NF-kappaB" she said. NF-kB is a cellular transcription factor that activates the expression of genes involved in inflammation. Shisler's lab was interested in determining whether MC160 also acted on NF-kB.

In their study -- funded by the National Institutes of Health -- Shisler and Daniel Brian Nichols, a doctoral student in microbiology, treated human embryonic kidney cells with cytokines known to activate NF-kB. Cytokines are chemicals made by immune cells that boost the immune system by stimulating inflammation to fight infectious pathogens.

"We found that the NF-kB levels were always lower in MC160-expressing cells," Shisler said. "This was an exciting new finding because no one had previously found a function for MC160. Currently, Brian and I think that this protein's role is to inhibit NF-kB activation in MCV-infected skin cells, to prevent cytokines from boosting the immune system. MC160 is probably helping the virus persist."

Upon further examination, Shisler and Nichols discovered that MC160 shuts down the NF-kB-triggered inflammatory response by degrading a subunit of t he immune system's I Kappa Kinase (IKK) complex. The normal function of IKK is to trigger the degradation of a protein that inhibits NF-kB activity. MC160 subsequently causes the IKK complex to fall apart to prevent the phosphorylation process that turns on NF-kB.

"Our findings regarding MC160 provide yet another example of how viruses inhibit NF-kB activation," Shisler said. "So we are starting to get a broader feeling that there is a common mechanism, that of inhibiting NF-kB activity, that all viruses are trying to utilize to survive in the host. What is interesting is that MC160 appears to be doing it in a completely novel way, than any identified before, by focusing on this IKK complex."

Shisler has obtained a patent to pursue the use of MC160, which is only made in skin cells and stays within them, as a therapeutic tool. Painful inflammatory responses caused by cytokine production in rheumatoid arthritis, Crohn's disease and similar maladies potentially could be cured by MC160.

It is hoped, she said, that the protein's large size (almost 60 kiloDaltons) can be reduced to smaller, activity-specific peptide regions. Doing so would simplify the preparation of a topical treatment that would inhibit painful inflammatory responses.

The molluscum contagiosum virus that produces MC160 is a distant relative of smallpox and causes a benign, short-lived skin infection in children and sexually active young adults. It is a common disease, with antibodies detected in up to 50 percent of populations tested in numerous studies. The lesions resemble chickenpox (a disease actually caused by a herpes virus) and are often confused as such. There is no treatment.

The incidence of MCV infections has increased with the rise of AIDS. MCV is an opportunistic infection in immunocompromised people, with MCV lesions growing very large and persisting for much longer periods, even years, in this population, Shisler said.

"This virus makes o ther proteins that dampen the immune response, but MC160 seems to be an important one," Shisler said. "Another goal is to design a drug that would override the activity of the protein as a cure for MCV."


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Source:University of Illinois at Urbana-Champaign


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