New research may lead to treatments for atherosclerosis

Nov 29 2004

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 NFêB and the expression of pro-inflammatory cytokines such as IL-1beta and TNFalpha." However, mice that lack IRAK1 can still activate NFêB, 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.