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The poly-\u03b3-<jats:sc>d<\/jats:sc>-glutamic acid (PGA) capsule is one of the major virulence factors of<jats:named-content content-type=\"genus-species\">B. anthracis<\/jats:named-content>, along with exotoxins. PGA enables<jats:named-content content-type=\"genus-species\">B. anthracis<\/jats:named-content>to escape phagocytosis and immune surveillance. Our previous study showed that PGA activates the human macrophage cell line THP-1 and human dendritic cells, resulting in the production of the proinflammatory cytokine interleukin-1\u03b2 (IL-1\u03b2) (M. H. Cho et al., Infect Immun 78:387\u2013392, 2010,<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/dx.doi.org\/10.1128\/IAI.00956-09\">http:\/\/dx.doi.org\/10.1128\/IAI.00956-09<\/jats:ext-link>). Here, we investigated PGA-induced cytokine responses and related signaling pathways in mouse bone marrow-derived macrophages (BMDMs) using<jats:named-content content-type=\"genus-species\">Bacillus licheniformis<\/jats:named-content>PGA as a surrogate for<jats:named-content content-type=\"genus-species\">B. anthracis<\/jats:named-content>PGA. Upon exposure to PGA, BMDMs produced proinflammatory mediators, including tumor necrosis factor alpha (TNF-\u03b1), IL-6, IL-12p40, and monocyte chemoattractant protein 1 (MCP-1), in a concentration-dependent manner. PGA stimulated Toll-like receptor 2 (TLR2) but not TLR4 in Chinese hamster ovary cells expressing either TLR2 or TLR4. The ability of PGA to induce TNF-\u03b1 and IL-6 was retained in TLR4<jats:sup>\u2212\/\u2212<\/jats:sup>but not TLR2<jats:sup>\u2212\/\u2212<\/jats:sup>BMDMs. Blocking experiments with specific neutralizing antibodies for TLR1, TLR6, and CD14 showed that TLR6 and CD14 also were necessary for PGA-induced inflammatory responses. Furthermore, PGA enhanced activation of mitogen-activated protein (MAP) kinases and nuclear factor-kappa B (NF-\u03baB), which are responsible for expression of proinflammatory cytokines. Additionally, PGA-induced TNF-\u03b1 production was abrogated not only in MyD88<jats:sup>\u2212\/\u2212<\/jats:sup>BMDMs but also in BMDMs pretreated with inhibitors of MAP kinases and NF-\u03baB. These results suggest that immune responses induced by PGA occur via TLR2, TLR6, CD14, and MyD88 through activation of MAP kinase and NF-\u03baB pathways.<\/jats:p>","DOI":"10.1128\/iai.00888-15","type":"journal-article","created":{"date-parts":[[2015,7,21]],"date-time":"2015-07-21T02:04:50Z","timestamp":1437444290000},"page":"3847-3856","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["The Poly-\u03b3-<scp>d<\/scp>-Glutamic Acid Capsule Surrogate of the Bacillus anthracis Capsule Is a Novel Toll-Like Receptor 2 Agonist"],"prefix":"10.1128","volume":"83","author":[{"given":"Jun Ho","family":"Jeon","sequence":"first","affiliation":[{"name":"Division of High-Risk Pathogen Research, Center for Infectious Diseases, National Institute of Health, Cheongju, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hae-Ri","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of High-Risk Pathogen Research, Center for Infectious Diseases, National Institute of Health, Cheongju, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min-Hee","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of High-Risk Pathogen Research, Center for Infectious Diseases, National Institute of Health, Cheongju, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ok-Kyu","family":"Park","sequence":"additional","affiliation":[{"name":"Division of High-Risk Pathogen Research, Center for Infectious Diseases, National Institute of Health, Cheongju, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jungchan","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yongin, Republic of Korea"},{"name":"Protein Research Center for Bioindustry, Hankuk University of Foreign Studies, Yongin, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gi-eun","family":"Rhie","sequence":"additional","affiliation":[{"name":"Division of High-Risk Pathogen Research, Center for Infectious Diseases, National Institute of Health, Cheongju, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2014.00083"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.9.5545"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2014.02.012"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-014-0300-9"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2011.08.016"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1006\/mpat.1993.1037"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2004.05.029"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.171.2.722-730.1989"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00706-06"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00741-07"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.035857-0"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00764-08"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01145-10"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200008033430506"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00046-08"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/35021228"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2011.05.039"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2008.02.005"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0807586"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.250476497"},{"key":"e_1_3_3_22_2","first-page":"BR149","article-title":"Induction of cytokine production in human T cells and monocytes by highly purified lipoteichoic acid: involvement of Toll-like receptors and CD14","volume":"8","author":"Ellingsen E","year":"2002","unstructured":"Ellingsen E, Morath S, Flo T, Schromm A, Hartung T, Thiemermann C, Espevik T, Golenbock D, Foster D, Solberg R, Aasen A, Wang J. 2002. 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