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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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