MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics.
Interleukin (IL)-1beta is a pluripotent proinflammatory cytokine that signals through the type-I IL-1 receptor (IL-1RI), a member of the Toll-like receptor family. In hypothalamic neurons, binding of IL-1beta to IL-1RI mediates transcription-dependent changes that depend on the recruitment of the cytosolic adaptor protein myeloid differentiation primary-response protein 88 (MyD88) to the IL-1RI/IL-1 receptor accessory protein (IL-1RAcP) complex through homomeric Toll/IL-1 receptor (TIR)-TIR interactions. Through design and synthesis of bifunctional TIR mimetics that disrupt the interaction of MyD88 with the IL-1RI/IL-1RAcP complex, we analyzed the involvement of MyD88 in the signaling of IL-1beta in anterior hypothalamic neurons. We show here that IL-1beta-mediated activation of the protein tyrosine kinase Src depended on a MyD88 interaction with the IL-1RI/IL-1RAcP complex. The activation of the protein kinase Akt/PKB depended on the recruitment of the p85 subunit of PI3K to IL-1RI and independent of MyD88 association with the IL-1RI/IL-1RAcP complex. These bifunctional TIR-TIR mimetics represent a class of low-molecular-weight compounds with both an antiinflammatory and neuroprotective potential. These compounds have the potential to inhibit the MyD88-dependent proinflammatory actions of IL-1beta, while permitting the potential neuronal survival supporting actions mediated by the MyD88-independent activation of the protein kinase Akt.
The Harold L. Dorris Neurological Institute, La Jolla, CA 92037, USA.
Christopher N
CN
Davis
Enrique
E
Mann
M Margarita
MM
Behrens
Svetlana
S
Gaidarova
Mitra
M
Rebek
Julius
J
Rebek
Tamas
T
Bartfai
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D007375:Interleukin-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt