Role of DAP12 in Regulating Inflammation
As was explained in the introduction to this issue, Toll-like receptors (TLRs) on and within macrophages are intimately involved in the inflammatory response. When the receptors recognize and lock onto a “pathogen associated molecular pattern," a series of chemical events begins that results in the release of proinflammatory cytokines. It is this signaling pathway and inflammatory response that arthritis researchers are trying to better understand and control. Jessica A. Hamerman, PhD, previously of University of California, San Francisco and now of Benaroya Research Institute of Seattle, Washington, is using her Arthritis Foundation research grant to study macrophages, TLRs and the chemical signals involved in turning on and turning off the production of proinflammatory cytokines.
What Problem Was Studied?
DAP12 is a signaling molecule found within macrophages. Although not a direct member of the TLR–inflammatory cytokine cascade, the DAP12 signaling pathway intersects with the TLR pathway in such a way that DAP12 can alter the TLR signal and influence the release of the cytokines tumor necrosis factor, interleukin-6 and interleukin-12. Hamerman’s team developed experiments to characterize the role of DAP12 in inflammatory reactions.
What Was Done In the Study?
Hamerman and colleagues performed a series of experiments on macrophages from specially bred mice that were incapable of producing DAP12 and macrophages from mice that could produce DAP12. They ran experiments on macrophages that had been removed from body (in vitro experiments) as well as experiments on the different types of mice (in vivo experiments). They expected that macrophages incapable of producing DAP12 would have no reaction, or a smaller reaction, to bacteria than would the normal macrophages because the signaling cascades within the cell would be interrupted.
What Were the Study Results?
Unexpectedly, the mice that could not produce DAP12 had a stronger reaction to the antigen than did the normal mice. The DAP12-deficient macrophages produced or released higher concentrations of tumor necrosis factor, interleukin-6 and interleukin-12 than did the normal macrophages. This result indicates that DAP12 may give inhibitory signals to the TLR chemical cascade rather than the stimulatory signals that the research team hypothesized. The team got the same results in both the in vitro and in vivo experiments.
What Does This Mean for People With Inflammatory Disorders?
Finding a molecule that may inhibit or turn off the inflammatory response in macrophages is an important step for scientists. Inflammatory disorders, such as rheumatoid arthritis, juvenile arthritis, diabetes, etc., may occur because these negative signals that tell the body to “turn off” inflammation may never get produced, or may not reach their targets. Identifying one of these inhibitory signals opens another path through which inflammation can be regulated with medication.
Because some of Hamerman’s results were contrary to results obtained by other research teams, and because she learned that DAP12-deficient macrophages produced not only greater concentrations of proinflammatory cytokines, but also greater concentrations of anti-inflammatory cytokines, her work with DAP12 will continue. Her lab has recently identified a receptor expressed in macrophages that works with DAP12 to inhibit inflammatory cytokine production. Eventually she hopes her diligence will lead to the discovery of a therapy that will tell the body to turn off the inflammatory signals when they are not needed.
Hamerman JA, Tchao NK, Lowell CA, Lanier LL. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nature Immunology 2005;6:579-586.
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