August 3, 2005
When innate immune cells encounter an invading pathogen, they utilize a family of type I transmembrane proteins called Toll-like receptors (TLRs) to initiate the host's immune response. Like reading Braille, TLRs recognize common molecular patterns present on or within the pathogen that results in triggering various biochemical responses within the immune cell. Previous work has established that TLRs can send intracellular signaling messages along a much studied internal signaling pathway called PI(3)K. What has remained unclear is how TLR-signaling specifies the subsequent release of either pro or anti inflammatory chemicals called cytokines, that can dictate the nature and magnitude of the host's inflammatory response. In the August issue of the journal Nature Immunology, NIDCR grantees and colleagues provide an important answer, showing that TLRs signal through "a central effector molecule" called glycogen synthase kinase 3 (GSK3), a well-known enzyme that once was mistakenly believed to influence glycogen metabolism only. The authors show that when GSK3 is turned off as TLRs are stimulated , GSK3 selectively augments anti-inflammatory cytokine production, while suppressing pro-inflammatory cytokines. In contrast, preventing the inactivation of GSK3 upon TLR-stimulation results in the enhancement of pro-inflammatory cytokines while concurrently suppressing anti-inflammatory cytokine production. This mechanistic information will be extremely helpful in learning to manipulate this key immune signal in a range of inflammatory conditions, including periodontal disease.