Investigators at the Hospital for Special Surgery identified two new targets, both part of the calcium-signaling pathway, for drugs aimed at controlling lupus by regulating interferons (IFNs).
IFNs have two major functions both mediated by proteins called STATs: first, they protect against viruses and second, they regulate immune responses, strengthening the responses and playing a role in autoimmunity. STAT1 mediates the autoimmune and inflammatory functions, and STAT2 mediates the virus protection function.
The investigators discovered that calcium specifically increases activation of STAT1 by interferons. The researchers then tested whether two kinase enzymes in the calcium-signaling pathway, CAMK and Pyk2, could be manipulated to control STAT1. In studies involving mice, the scientists showed that blocking these enzymes with a drug called KN-93 regulated the amount of STAT1, but not STAT2 activation.
“What we found was that these kinases that are regulated by calcium actually regulate the strength of activation of STAT1 by the interferons, but they do not regulate the strength of activation of STAT2,” says Lionel Ivashkiv, M.D., director of basic research at Hospital for Special Surgery and study leader. “We tested that in an animal model of lupus and we were able to show, in vivo, that you can suppress STAT1 activation by inhibiting the calcium-dependent kinases.”
The study was published online in Nature Immunology on December 16.