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* Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, and
Department of Pediatrics,
Department of Microbiology, Immunology, and Tropical Medicine, and
Department of Biochemistry and Molecular Biology, George Washington University School of Medicine, Washington, DC
Gangliosides, sialic acid-containing glycosphingolipids present in the outer leaflet of plasma membranes, are produced at high levels by some tumors, are actively shed into the tumor microenvironment, and can be detected in high concentrations in the serum of cancer patients. These tumor-shed molecules are known to be immunosuppressive, although mechanisms remain to be fully elucidated. In this study, we show that membrane enrichment of human monocytes with purified exogenous gangliosides potently inhibits ligand-induced activation and proinflammatory cytokine production induced by a broad range of TLRs, including TLR2, TLR3, TLR6, and TLR7/8, in addition to a previously identified inhibitory effect on TLR4 and TLR5. Inhibition of TLR activation is reversible, with complete restoration of TLR signaling within 6–24 h of washout of exogenous gangliosides, and is selective for certain gangliosides (GM1, GD1a, and GD1b), whereas others (GM3) are inactive. To characterize the inhibition, we assessed the expression of the TLR signaling pathway inhibitor, IL-1 receptor associated kinase-M (IRAK-M). In response to ganglioside enrichment alone, we observed striking up-regulation of IRAK-M in monocytes, but without concomitant proinflammatory cytokine production. This contrasts with endotoxin tolerance, in which IRAK-M up-regulation follows proinflammatory cytokine expression caused by LPS exposure. We hypothesize that ganglioside treatment induces a state of tolerance to TLR signaling, leading to blunted activation of innate immune responses. In the tumor microenvironment, shed tumor ganglioside enrichment of APC membranes may likewise cause these cells to bypass the normal TLR signaling response and progress directly to the inhibitory state.
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1 This work was supported by National Institutes of Health Grant R01 CA42361 (to S.L.) and by The Children’s Cancer Foundation. K.D.S. is the recipient of an National Institute of Child Health and Human Development Child Health Research Scholar Award (K12 HD001399).
2 W.S. and K.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Stephan Ladisch, Center for Cancer and Immunology Research, Children’s National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010. E-mail address: sladisch{at}cnmc.org
4 Abbreviations used in this paper: DC, dendritic cell; IRAK-M, interleukin-1 receptor associated kinase-M; LTA, lipoteichoic acid; poly(I:C), poly (cytidylic-inosinic) acid; siRNA, short interfering RNA.
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