New findings in innate immunity may lead to treatments for atherosclerosis

Scientists are one step closer to deciphering the molecular signaling process controlling innate immunity with the
discovery that a molecule called IRAK1 regulates the expression of the anti-inflammatory cytokine IL-10. Because
atherosclerosis patients often have elevated IL-10 levels, IRAK1 may be a viable target for developing therapeutics for
atherosclerosis.


The research appears as the "Paper of the Week" in the December 3 issue of the Journal of Biological Chemistry, an American
Society for Biochemistry and Molecular Biology journal.


Innate immunity is the body's first response to infection, and it plays a major role in regulating infection, inflammation,
cell growth, and apoptosis. During an innate immune reaction, macrophages, dendritic cells, and epithelial cells use a set of
transmembrane receptors called Toll-like receptors (TLRs) to initiate signaling cascades.


"TLRs can sense diverse environmental cues and send signals downstream to a family of interleukin-1 receptor associated
kinases (IRAKs). These IRAKs then activate and/or regulate specific cytokine gene expression," explains Dr. Liwu Li of the
Wake Forest University School of Medicine.


However, the specificity of the TLR signaling process is not clearly understood. "In the past," says Dr. Li, "it was thought
that all IRAKs may play a somewhat redundant role in regulating the nuclear transcription factor NFкB and the expression of
pro-inflammatory cytokines such as IL-1beta and TNFalpha." However, mice that lack IRAK1 can still activate NFкB, suggesting
that IRAK1 may be involved in other activities.


Dr. Li and his colleagues discovered that IRAK1 actually activates a molecule called Signal Transducer and Activator of
Transcription 3, or Stat3, which in turn activates expression of the anti-inflammatory cytokine IL-10. The scientists also
found that IRAK1 can translocate into the nucleus and regulate the nuclear transcription of proteins. "Our finding sets IRAK1
apart from other IRAKs and elucidates a novel pathway in innate immunity regulation," says Dr. Li.


Because atherosclerosis patients usually have elevated serum IL-10 levels, the scientists also looked at IRAK1 levels in
blood from atherosclerosis patients. They found that IRAK1 is modified and localized to the nucleus in these patients,
indicating a possible link between IRAK1 regulation and the pathogenesis of atherosclerosis.


"Inflammation and infection have been increasingly shown to play a significant role in the pathogenesis and/or resolution of
atherosclerosis," explains Dr. Li. "Anti- inflammatory cytokines such as IL-10 may serve as a self protective mechanism to
prevent excessive inflammation and contribute to plaque stability. Indeed, patients with higher IL-10 serum levels have a
better chance of recovery. Therefore, elevated IRAK1 modification and IL-10 levels observed in atherosclerosis patients may
be a compensatory and self-protective mechanism."















Manipulating innate immunity may eventually be a therapeutic strategy for treating atherosclerosis. "Our study, as well as
others, indicates that innate immunity alteration plays a critical role in either the pathogenesis or resolution of
atherosclerosis. IRAK1 may provide a viable target for developing therapeutic interventions for atherosclerosis. Compounds or
strategies directed at preventing or enhancing IRAK1 modification and nuclear entry may hold great promise in treating
atherosclerosis," concludes Dr. Li.


Besides atherosclerosis, alterations in innate immunity can cause diabetes, cancer, and numerous other inflammatory
disorders. Further understanding of the innate immunity process may lead to development of therapies for these diseases as
well.


The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers
received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be
accessed directly from the home page of the Journal of Biological Chemistry online at jbc.


The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization
with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and
universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry.



Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for
Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through
its publications, the Journal of Biological Chemistry, The Journal of Lipid Research, Molecular and Cellular Proteomics, and
Biochemistry and Molecular Biology Education, and the holding of scientific meetings.


For more information about ASBMB, see the Society's website at asbmb.


Contact: Nicole Kresge

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301-634-7415

American Society for Biochemistry and Molecular Biology