Citizen Participation in Urban Services: the Administration of a Community-Based Crime Prevention Program

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68929/2/10.1177_089976407800700105.pd

Territoriality, Identity and Conduct: A Study of an Inner City Slum With Special Reference to Street Corner Groups

545 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1966.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

MyD88-Dependent SHIP1 Regulates Proinflammatory Signaling Pathways in Dendritic Cells after Monophosphoryl Lipid A Stimulation of TLR4

We previously showed that monophosphoryl lipid A (MLA) activates TLR4 in dendritic cells (DCs) in a Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF)-biased manner: MLA produced from Salmonella minnesota Re595 induced signaling events and expression of gene products that were primarily TRIF dependent, whereas MyD88-dependent signaling was impaired. Moreover, when tested in TRIF-intact/MyD88-deficient DCs, synthetic MLA of the Escherichia coli chemotype (sMLA) showed the same activity as its diphosphoryl, inflammatory counterpart (synthetic diphosphoryl lipid A), indicating that TRIF-mediated signaling is fully induced by sMLA. Unexpectedly, we found that the transcript level of one proinflammatory cytokine was increased in sMLA-treated cells by MyD88 deficiency to the higher level induced by synthetic diphosphoryl lipid A, which suggested MyD88 may paradoxically help restrain proinflammatory signaling by TRIF-biased sMLA. In this article, we demonstrate that sMLA induces MyD88 recruitment to TLR4 and activates the anti-inflammatory lipid phosphatase SHIP1 in an MyD88-dependent manner. At the same time, MyD88-dependent signaling activity at the level of IL-1R-associated kinase 1 is markedly reduced. Increased SHIP1 activity is associated with reductions in sMLA-induced I kappa B kinase alpha/beta and IFN regulatory factor 3 activation and with restrained expression of their downstream targets, endothelin-1 and IFN-beta, respectively. Results of this study identify a pattern that is desirable in the context of vaccine adjuvant design: TRIF-biased sMLA can stimulate partial MyD88 activity, with MyD88-dependent SHIP1 helping to reduce proinflammatory signaling in DCs. The Journal of Immunology, 2011, 186: 3858-3865