Doubly Safe Activation


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A team of Weizmann Institute scientists show that the immune system employs “dual key” activation to launch a potent antiviral weapon

'Dual key' activation, in which two people must act in concert to launch a weapon, is often installed to safeguard highly destructive arms. New research at the Weizmann Institute of Science shows that cells may employ this strategy as well before launching certain potent weapons of the immune system.
Interferons, which were discovered 50 years ago, are the body’s first line of defense against viral attack. They are produced in cells that have been invaded by viruses, and from there, they spread out to warn other cells to prepare for the impending onslaught. These signaling molecules are associated with the symptoms – fever and inflammation – of viral infections such as the flu. Three main interferon families have been identified, and they are known by the Greek letters alpha, beta and gamma. Interferons alpha and beta are very similar: They have nearly identical modes of action and even attach to the same receptor on the cell wall. Interferon gamma is different from these two. It has its own receptor and, in addition to its immediate antiviral actions, is involved in a number of crucial activities in the immune system, including a step known as antigen presenting, which enables the immune system to tailor antibodies to a specific enemy, and the activation of certain immune cells that engulf and destroy pathogens.
But new findings published recently in the Proceedings of the National Academy of Sciences (PNAS), show that the third type of interferon often doesn’t act alone. The Weizmann Institute team headed by Prof. Menachem Rubinstein of the Molecular Genetics Department, which included Dr. Vladimir Hurgin, Dr. Daniela Novick and Dr. Ariel Werman, together with Prof. Charles Dinarello of the University of Colorado, USA, found that another molecule that’s produced inside cells, interleukin 1- alpha (IL-1 alpha), must be present for initiating many of the basic activities of interferon gamma.
While molecules have been known to work together in this way, the collaboration between interferon gamma and IL-1 alpha came as something of a surprise to scientists: Although the molecules are produced in two independent systems, they match like two halves of a key: IL-1 alpha doesn’t affect alpha or beta interferons, and interferon gamma seems to work specifically with IL-1 alpha. They were also surprised because interferons, which form the basis of a number of drugs (mainly alpha and beta), have been widely studied, yet the connection between these two molecules had not been seen before. Rubinstein’s explanation is that previous interferon experiments had been performed with cells that produced their own IL-1 alpha in the lab culture, and thus scientists had missed its effect.
Interferon gamma and IL-1 alpha have a synergistic effect on each other, activating around 500 genes, including those that bring about the fever and muscle aches. Rubinstein: 'The antiviral activity of interferon gamma comes at a high cost. We think this is the reason the body uses a ‘dual key’ system – to provide an extra level of security before paying that price.'

Prof. Menachem Rubinstein is the incumbent of the Maurice and Edna Weiss Professorial Chair of Cytokines Research.