Editors' ChoiceImmunology

GSK-3β Masters TLR4 Responses

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Science Signaling  11 Nov 2008:
Vol. 1, Issue 45, pp. ec385
DOI: 10.1126/scisignal.145ec385

Stimulation of Toll-like receptor 4 (TLR4) by the bacterial product lipopolysaccharide (LPS) activates signaling pathways that are dependent and independent of the adaptor protein myeloid differentiation marker 88 (MyD88). MyD88-dependent signaling results in the production of proinflammatory cytokines, whereas MyD88-independent signaling, which involves the adaptor proteins TRAM and TRIF, results in the production of the type I interferon (IFN), IFN-β. Activation of TLR4 also triggers the phosphorylation [by phosphoinositide 3-kinase (PI3K)] and inactivation of glycogen synthase kinase-3β (GSK-3β), which modulates the types of cytokines produced in response to LPS through TLR4-MyD88 signaling. Wang et al. investigated the role of GSK-3β in MyD88-independent, TLR4-stimulated production of IFN-β. Stimulation of macrophages from MyD88-deficient mice with LPS resulted in a similar extent of phosphorylation of GSK-3β as was observed in macrophages from wild-type mice. LPS-stimulated macrophages in which GSK-3β was inhibited or depleted produced more IFN-β than did LPS-stimulated control macrophages, whereas expression of a constitutively active form of GSK-3β inhibited IFN-β production. The authors found that inhibition of GSK-3β resulted in the increased nuclear abundance of the transcription factor c-Jun, which is required for expression of the gene encoding IFN-β. In the context of depleted c-Jun, inhibition of GSK-3β activity did not increase the production of IFN-β in LPS-stimulated cells. Mice that received a GSK3 inhibitor before a sublethal dose of LPS produced more IFN-β than did LPS-treated control mice. Thus, GSK-3β appears to have an important role in modulating both MyD88-dependent and MyD88-independent responses to the TLR4 ligand LPS.

H. Wang, C. A. Garcia, K. Rehani, C. Cekic, P. Alard, D. F. Kinane, T. Mitchell, M. Martin, IFN-β production by TLR4-stimulated innate immune cells is negatively regulated by GSK3-β. J. Immunol. 181, 6797-6802 (2008). [PubMed]

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