title: Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment.
abstract: S100A8/A9 is a major component of the acute phase of inflammation, and appears to regulate cell proliferation, redox regulation and chemotaxis. We previously reported that S100A8/S100A9 are upregulated in the premetastatic lung. However, the detailed mechanisms by which S100A8 contributes to tumor progression have not been elucidated. In this study, we investigated the TLR4/MD-2 dependency by S100A8 on tumor progression. We found that S100A8 (2-89) peptide stimulated cell migration in a manner dependent on TLR4, MD-2 and MyD88. The S100A8 (2-89) peptide also activated p38 and NF-κB in TLR4-dependent manner. The peptide induced the upregulation of both IL-6 and Ccl2 in peritoneal macrophages obtained from wild-type mice, but not TLR4-deficient mice. We then investigated the responsible region of S100A8 for TLR4/MD-2 binding by a binding assay, and found that C-terminal region of S100A8 binds to TLR4/MD-2 complex. To further evaluate the TLR4 dependency on tumor microenvironment, Lewis lung carcinoma-bearing mice were treated with Eritoran, an antagonist of TLR4/MD-2 complex. We found that both tumor volume and pulmonary recruitment of myeloid-derived suppressor cells were reduced with the treatment of Eritoran for five consecutive days. Eritoran reduced the development of tumor vasculature, and increased tumor-infiltration of CD8(+) T-cells. Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment.
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Deguchi
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: U
authors.initials: U
authors.lastname: Ohto
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takemura
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kitao
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Akashi-Takamura
authors.affiliation: Division of Infections Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Maru
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D040501:Calgranulin A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004187:Disaccharides / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D051218:Lymphocyte Antigen 96 / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011485:Protein Binding / Q000235:genetics; D013403:Sugar Phosphates / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004187:Disaccharides; D015850:Interleukin-6; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; D013403:Sugar Phosphates; D051197:Toll-Like Receptor 4; C512420:eritoran; D048051:p38 Mitogen-Activated Protein Kinases