February 05, 2005
How an AIDS-Related Cancer Unleashes Inflammation
Although new HIV treatments have drastically reduced the incidence
of Kaposi's sarcoma in developed countries, it remains a health threat
in many developing countries. Now, researchers have discovered one way
that Kaposi's sarcoma — a cancer-like viral disease traditionally
associated with AIDS — triggers severe inflammation.
Don Ganem, a Howard Hughes Medical Institute (HHMI) investigator,
and HHMI associate Craig McCormick, who are both at the University of
California, San Francisco, published their findings in the February 4,
2005, issue of the journal Science.
“While there are many genes in the viral genome that are capable of inducing cytokine production, the mechanism underlying this induction has remained unknown.”
Donald Ganem
Ganem and McCormick dedicated the Science article to the
memory of Robert Sadler, a former HHMI associate in Ganem's lab who
discovered kaposin B. Sadler was killed in 1999 by stray bullets fired
into a San Francisco nightclub.
According to Ganem, early studies of Kaposi's sarcoma (KS) indicated
that the abnormal growth of infected cells required the overproduction
of cytokines — immune system proteins that trigger the cell's
inflammatory response. A central question, he said, has been how does
the Kaposi's sarcoma-associated herpesvirus that causes KS initiate
cytokine production?
"While there are many genes in the viral genome that are capable of
inducing cytokine production, the mechanism underlying this induction
has remained unknown," said Ganem.
In their studies, McCormick and Ganem concentrated on one protein
called kaposin B, which was discovered in Ganem's laboratory, but whose
function remained unknown. "The sequence of the kaposin B gene is very
unusual; there's no homology to any known gene," said Ganem. "So, we
had no clue as to what the protein did. Since it was a very simple
protein, we believed that it had no enzymatic function itself, but
acted by binding to or activating other proteins," he said.
Thus, the researchers conducted experiments in which they isolated
proteins that bound with kaposin B in the cell. That screening revealed
that kaposin B binds to a protein called MK2, which is known to play a
role in boosting cytokine production.
In further experiments, they discovered that the binding of kaposin
B activated MK2, leading to higher levels of cytokines in the cell.
Activated MK2 does this by prolonging the stability of cytokine
messenger RNA — the genetic blueprint for cytokine proteins. The
longer these messenger RNAs remain in the cell, the more cytokine
proteins the cell's protein-making machinery is able to synthesize,
said Ganem.
The activation of MK2 also increases production of
blood-vessel-forming, or angiogenic factors, including the protein
VEGF. The activation of angiogenesis pathways by kaposin B fits with
observations made in patients with KS, Ganem noted. "If you examine
lesions in a patient with KS, you'll see that they are visibly red
because of all the new blood vessels that KS produces," he said.
In cell culture studies, the researchers found evidence of an
“activation loop,” by which kaposin B activation of MK2
promotes even further MK2 activity by other proteins. The
over-production of cytokines resulting from kaposin B's binding to MK2
creates inflammation that in turn activates the regulatory protein p38.
p38, in turn, further increases activation of MK2.
"We still don't know the mechanism by which kaposin B activates
MK2," said Ganem. "Nor do we understand how this activation leads to
activation of the upstream regulator of MK2, which is p38. Thus, while
we now understand the biology of this inflammation, the details of the
biochemistry still need to be worked out," he said.
While the new knowledge of kaposin B's role will contribute to
understanding how the responsible virus produces cytokines, there are
likely other mechanisms at work as well, Ganem emphasized. Other viral
genes are also known to be involved in cytokine pathways, he said.
Developing countries — where HIV treatments are not readily
available — will be most likely to benefit from potential new
treatments for KS that involve inhibiting cytokine production, Ganem
said. “KS has become a less urgent threat in developed countries,
because two factors are needed for KS lesions — viral infection and
immunodeficiency. Effective new treatments for HIV have strikingly
reduced the immunodeficiency factor in developed countries; so new
cases of KS have gone down by 90 percent since 1996,” he said.
There are also forms of KS not linked to HIV, Ganem added, and these
studies could also lead to new treatments for those forms of the
illness.
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