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Cytokine resistance contributes to pathology of type 2 diabetes
Diana Yates,
Life Sciences Editor
217-333-5802; diya@illinois.edu
|
Released
6/14/2007
CHAMPAIGN, Ill. —
In a study appearing this month in the Journal of Immunology, researchers
at the University of Illinois describe how an impaired anti-inflammatory
response plays a role in the pathology of type 2 diabetes.
Type 2 diabetes is classified as a metabolic disorder, but a growing
number of researchers are beginning to think of it also as a disease
of the innate immune system. Inflammation, a key component of the early
immune response, is chronically elevated in people with type 2 diabetes.
While the pro-inflammatory pathways of type 2 diabetes have received
much attention, the anti-inflammatory side of the equation is less well
known.
The new study focused on a number of cytokines, protein signals that
bind to specific receptors on cells and set off a cascade of biochemical
reactions within the cell. Interleukins, interferons, tumor necrosis
factors and some growth factors are among the cytokines that direct
many aspects of the immune response. Cytokines are secreted by many
types of cells, including the immune cells known as macrophages.
In earlier studies, the researchers had shown that macrophages in diabetic
and obese (diabese) mice secrete more pro-inflammatory and less anti-inflammatory
cytokines than those of nondiabese mice. The team, led by pathology professor and department head Gregory Freund, also had demonstrated
that human monocytes cultured under type 2 diabetic conditions had impaired
interleukin-4 signaling. Interleukin 4 (IL-4) is an important player
in the immune response in that it steers macrophages toward the production
of other anti-inflammatory cytokines. It also inhibits secretion of
the pro-inflammatory cytokines.
When IL-4 binds to its receptor on a target cell, it sets off one of
two cascades of intracellular events.
The first of these signal transduction pathways, the Jak-STAT pathway,
is well studied and well understood. The second, called the insulin
receptor substrate 2 / phosphatidylinositol-3 kinase (IRS-2/PI3K) pathway,
was more of a mystery, and of greater interest to Freund and his colleagues.
What drew them to this pathway was its potential role in the anti-inflammatory
response, and its similarity to the cascade initiated when cells respond
to insulin.
“One of the actions of diabetes is to create intracellular insulin
resistance,” Freund said. “Some of the cytokines that work
on cells share the same pathways as the insulin receptor.” Since
diabetes causes insulin resistance, Freund said, “shouldn’t
there be a resistance to cytokines, too? And that is what we found.”
The research team showed, for the first time, that the IRS-2 signaling
arm of the interleukin-4 pathway directed the up-regulation of a key
anti-inflammatory molecule in primary macrophages, and that this pathway
was disrupted in type 2 diabetic conditions. They also showed that the
loss of IL-4 function in diabese mice caused chronic over-expression
of an important suppressor of cytokine signaling (SOCS) protein. This
SOCS-3 protein aborts the cascade of events that normally leads to insulin
uptake and/or cytokine signaling in a balanced inflammatory response.
This study supports earlier findings that inflammation is a key part
of the pathology of diabetes, Freund said. Pro-inflammatory cytokines
are elevated in type 2 diabetes, but the anti-inflammatory mechanisms
are also impaired, leading to a multitude of major and minor health
issues in the diabese.
“They get a cold. They get injured. Something happens. And it’s
worse in those people with obesity or diabetes and lasts longer than
it does in others,” Freund said. “Why? The imbalance may
be the elevation in pro-inflammation. But it probably also includes
a loss of anti-inflammatory function.”
This research was supported by grants from the National Institutes of
Health, American Heart Association, and the U. of I. Agricultural Experiment
Station.
Editor’s notes: To reach Gregory Freund,
call 217-244-8839; e-mail: freun@illinois.edu.
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