MyD88-dependent SHIP1 regulates proinflammatory signaling pathways in dendritic cells after monophosphoryl lipid A stimulation of TLR4

• Published in: The Journal of immunology (1950) 2011-04, Vol.186 (7), p.3858-3865
• Main Authors: Cekic, Caglar, Casella, Carolyn R, Sag, Duygu, Antignano, Frann, Kolb, Joseph, Suttles, Jill, Hughes, Michael R, Krystal, Gerald, Mitchell, Thomas C
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - antagonists & inhibitors; Adjuvants, Immunologic - metabolism; Adjuvants, Immunologic - physiology; Animals; Bone Marrow Cells - immunology; Bone Marrow Cells - microbiology; Bone Marrow Cells - pathology; Dendritic Cells - immunology; Dendritic Cells - microbiology; Dendritic Cells - pathology; Escherichia coli; Escherichia coli - immunology; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Inflammation Mediators - physiology; Inositol Polyphosphate 5-Phosphatases; Lipid A - analogs & derivatives; Lipid A - physiology; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myeloid Differentiation Factor 88 - deficiency; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - physiology; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - deficiency; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - physiology; Salmonella - immunology; Salmonella minnesota; Signal Transduction - genetics; Signal Transduction - immunology; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 4 - metabolism; Toll-Like Receptor 4 - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1001034

We previously showed that monophosphoryl lipid A (MLA) activates TLR4 in dendritic cells (DCs) in a Toll/IL-1R domain-containing adaptor inducing IFN-β (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 IκB kinase α/β and IFN regulatory factor 3 activation and with restrained expression of their downstream targets, endothelin-1 and IFN-β, 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.