TLR4 Gene Found to Protect Against Tumor Development
A new study finds that a gene which plays an important role in immune function,
known as toll-like receptor 4 (TLR4), may also play a critical role in suppressing
chronic lung inflammation and tumor development in mice.
"We know that chronic inflammation predisposes people to many types of cancer," says
NIH Director Elias Zerhouni, M.D. "By using this new information we may be able
to suppress chronic inflammation and reduce our Nation's cancer burden."
In the December 7, 2005 issue of the Journal of the National Cancer Institute,
researchers at the National Institute of Environmental Health Sciences (NIEHS),
a part of the National Institutes of Health, report that mice prone to lung cancer
that had TLR4 removed or altered had 60 percent more tumors than mice that had
intact receptors, illustrating a new protective role for this gene. There were
no differences in overall tumor size or structure between the mice. TLR4 is part
of what immunologists refer to as the “innate immune system” which acts as the
body’s first line of defense against harmful substances.
Researchers explain the immune system actually is comprised of two components
or systems, the innate and the acquired. The innate system can be thought of
as the way the body is naturally programmed to respond, forming the front line
of defense against infection. The acquired depends on the development of antibodies
and other systems to recognize pathogens and other foreign objects that might
upset the body’s ability to fight off diseases. Understanding more about how
the innate system works will help inform how the more complex, acquired system
works.
“We have recently learned a lot about TLR4, its different mutations, and the
role they play in immunity,” said David A. Schwartz, MD, the NIEHS Director, “but
discovering this novel function of TLR4 in tumor biology may provide new therapeutic
targets for many chronic diseases, including cancer.”
“We can’t attribute the number of tumors per mouse to TLR4 alone, but it accounts
for a significant portion of it,” said Steven Kleeberger, Ph.D., Chief, Laboratory
of Respiratory Biology at NIEHS, where the research was conducted. The researchers
administered a preservative known to cause lung inflammation to the mice to determine
the role of TLR4 in inflammation. Primary tumor formation also was measured in
mice known to have cancer. Mice with both functional and altered TLR4 were used
in all protocols.
“TLR4 acts like a brake of a car,” Kleeberger said. “If you take the brake or
receptor away, you see more increases in tumor development, more inflammation
and more mortality
Previous research indicated an association between chronic lung inflammation
and lung cancer, but the mechanisms are not well understood. Chronic bronchitis
and asthma, for example, are known to heighten the risk of lung cancer. Inflammation
has been implicated as a contributing factor in several human cancers, including
lung cancer. Therefore, researchers wanted to see if one of the well known receptors
in the immune system, the TLR4, played a role in the development of cancer in
an animal model.
“What we found is the innate immune system, particularly TLR4, plays a critical
role in protecting against the development of tumors and chronic inflammation,” said
Alison Bauer, Ph.D., of NIEHS and lead author on the paper. “It suggests that
targeting the innate immune system may be a useful tool in fighting a variety
of human diseases, including cancer.”
“This mouse model provides us with the rationale to ask whether the innate immune
system might be involved in lung cancer in humans,” said Dr. Schwartz. “We are
clearly finding that a better understanding of innate immunity will provide us
with new ways to fight off many diseases.”
NIEHS, a component of the National Institutes of Health, supports research
to understand the effects of the environment on human health. For more information
on environmental health topics, please visit our website at http://www.niehs.nih.gov/home.htm.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov. |