These findings open many interesting
medical possibilities to influence metabolic rates, disease progression, and life
span. We will study which molecular and cellular adjustments are responsible for
the longevity of these mice.
No morphologic or immunohistochemical
markers are available for the visualization of warm-sensitive neurons. This lack
severely limits the possibility of studying these neurons. Using electrophysiologic
studies and the pyrogenic substances prostaglandin E2 and IL-1β,
we identified electrophysiologic, morphologic, and immunohistochemical markers of
warm-sensitive neurons. IL-1β
can directly affect the warm-sensitive neurons (Fig. 2) via the Toll signaling pathway
that involves MyD88 adapters. In another project, we are synthesizing compounds
that can interrupt this signaling.
IL-1β is the most potent pyrogen known; 0.5 pmol causes full fever response in humans. We found that IL-1 type 1 receptors (IL-1R1) are present on many anterior hypothalamic neurons that affect warm sensitivity. Toll-like receptor signaling occurs via recruitment of small adaptor molecules. An adaptor molecule for IL-1R1 is the small cytosolic protein MyD88. MyD88 interacts with the receptor via a homotypic interaction between large protein domains called TIR domains. Because IL-1 signaling plays a key role in severe chronic inflammatory diseases such as rheumatic arthritis, there is a strong focus on blocking IL-1 signaling.
When the crystal structure of the first TIR domain was resolved, we reasoned that the BB-loop of 3 amino acids, phenylalanine-valine-proline, might be one of the homotypic sites of TIR-TIR interactions. We designed and synthesized a set of BB-loop MyD88 mimics, of which the best studied is AS-1, and a set of dimeric ligands like EM163 (Fig 3). We showed that AS-1 and EM163 can block IL-1 signaling in cellular systems; they can inhibit the physical interaction as signified by coimmunoprecipitation of IL-1R1 with MyD88, and, even more important. they can attenuate in vivo the IL-1induced fever response and suppress the formation of inflammatory mediators. These compounds constitute a novel class of anti-inflammatory molecules useful in the treatment of rheumatic arthritis and psoriasis.
Bartfai, T., Lees, G.V. Drug Discovery: From Bedside to Wall Street. Academic Press, San Diego, 2006.
Davis, C.N., Mann, E., Behrens, M.M., Gaidarova, S., Rebek, M., Rebek, J., Jr., Bartfai, T. MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics. Proc. Natl. Acad. Sci. U. S. A. 103:2953, 2006.
Davis, C.N., Tabarean, I., Gaidarova, S., Behrens, M.M., Bartfai, T. IL-1β induces a MyD88-dependent and ceramide-mediated activation of Src in anterior hypothalamic neurons. J. Neurochem. 98:1379, 2006.
Sanchez-Alavez, M., Tabarean, I.V., Behrens, M.M., Bartfai, T. Ceramide mediates the rapid phase of febrile response to IL-1β. Proc. Natl. Acad. Sci. U. S. A. 103:2904, 2006.
Tabarean, I.V., Conti, B., Behrens, M., Korn, H., Bartfai, T. Electrophysiological properties and thermosensitivity of mouse preoptic and anterior hypothalamic neurons in culture. Neuroscience 135:433, 2005.
Tabarean, I.V., Korn, H., Bartfai, T. Interleukin-1β induces hyperpolarization and modulates synaptic inhibition in preoptic and anterior hypothalamic neurons. Neuroscience 41:1685, 2006.