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Inside inflammation
How an enzyme called Csk controls the body’s immune response — and may answer questions about inflammation’s role in cancer, asthma and heart disease
BY LYNN LOVE
Inflammation, it seems, is a hot topic these days. Even on the cover of Time magazine. Its February 23 story implicates the biological process of inflammation — the body’s own defense against microbe invaders — in diseases from diabetes and cancer to asthma and heart disease. “Hardly a week goes by without the publication of yet another study uncovering a new way that chronic inflammation does harm to the body,” the Time journalists wrote.
While physicians are struggling to understand how inflammation is linked to disease, Rockefeller scientists, in their typical fashion, are focusing on what goes on at the most basic molecular level.
Sasha Tarakhovsky, head of the Laboratory of Lymphocyte Signaling, working with a team at the Windeyer Institute at University College London, has now discovered an enzyme that halts inflammation in mice.
Their findings, which were featured as the lead article in the February issue of Immunity, may prove to be an important milestone in the understanding of how inflammation may contribute to disease.
Inflammation isn’t always bad. When the body responds to the presence of a pathogen, early responder immune system cells called granulocytes migrate amoeba-style into the infected tissue. Once in place, these granulocytes engulf and destroy invaders.
This process, the basic cycle of inflammation, fights microbes of all types before the body’s adaptive immune response, the second level, kicks in. But if unchecked, the inflammation response has devastating potential. If allowed to continue indefinitely, it can cause serious consequences such as sepsis and death.
Tarakhovsky’s studies now show that it’s up to an enzyme called Csk to serve as the crucial check on the system. Enzymes play important facilitating roles in the body: they drive metabolism, replicate DNA, read genes, convey signals from the outside of the cell to their destinations within and perform many other functions. In the case of inflammation, Csk tells early responder immune cells when to stand down.
“The important role of Csk is an unexpected finding,” says Tarakhovsky. “The enzyme is part of a family of enzymes we know to be involved with a different kind of immune system function. Its presence in inflammation runs counter to what we would have predicted.”
Tarakhovsky should know. He’s one of the world’s experts on immune system signaling pathways, and in particular, Csk and its family of enzymes, known as the Src family kinases (SFKs). Because Tarakhovsky has been so successful in understanding the role of Csk in T cells, Jürgen Roes and Richard Thomas, both immunologists based in London, sought his expertise to determine whether Csk plays a role in inflammation.
“We know that Csk is a negative regulator of many processes, and that it is a key enzyme in the adaptive immune response,” Tarakhovsky explains. “We wanted to find out whether Csk plays an important role in innate immune response.” (The innate immune response is an immediate defense against potentially harmful microbes, while the adaptive immune response is a more versatile set of defenses that often prevent reinfection with the same pathogen.)
To find out, the scientists genetically inactivated Csk in granulocytes, the diverse collection of white blood cells that initially migrate to sites of infection or inflammation. Inactivating Csk entirely from a living organism, such as a mouse, is not possible. Instead, Tarakhovsky and his colleagues’ skill at creating conditional knockout mice using a site-specific inactivation method called Cre-loxP recombination aided the research. In mice without Csk in their granulocytes, the inflammatory response was abnormal. These Csk-deficient mice developed spontaneous inflammation; their granulocytes were hypersensitive and overly aggressive.
In other words, without Csk, the biochemistry of inflammation runs amok.
“Csk limits the biochemical signaling that tells cells to change their shape and texture from non-adhesive to adhesive — the enzyme restores non-inflammatory status to an anatomical locale," Tarakhovsky says.
What’s more, Csk is found in every organism from hydra to humans, suggesting a crucial role that may be similar across many species.
Now the research team wonders whether some people have a stronger or weaker genetic predisposition to the Csk signal. Targeting drugs to Csk or the enzymes it inhibits may be a possibility in establishing better inflammatory controls in the immune system.
While Tarakhovsky and his team study the signaling of immune system cells, the research group at UCL plans to continue the search for inhibitory mechanisms of inflammation which, in concert with Csk, ensure that the body’s powerful initial response to microbes stays focused.

March 26, 2004



 

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