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To understand the mechanisms of immune regulation employed by the host to control this inflammatory response, we focused our studies on adrenomedullin, a peptide produced in response to bacterial stimuli that exhibits antimicrobial activity and regulates inflammatory responses by modulating the expression of inflammatory cytokines. Specifically, we investigated the effect of<jats:italic>B. burgdorferi<\/jats:italic>on the expression of adrenomedullin as well as the ability of adrenomedullin to dampen host inflammatory responses to the spirochete. The concentration of adrenomedullin in the synovial fluid of untreated Lyme arthritis patients was elevated compared with that in control osteoarthritis patient samples. In addition, coculture with<jats:italic>B. burgdorferi<\/jats:italic>significantly increased the expression of adrenomedullin in RAW264.7 macrophages through MyD88-, phosphatidylinositol 3-kinase (PI3-K)-, and p38-dependent signaling cascades. Furthermore, the addition of exogenous adrenomedullin to<jats:italic>B. burgdorferi-<\/jats:italic>stimulated RAW264.7 macrophages resulted in a significant decrease in the induction of proinflammatory cytokines. Taken together, these results suggest that<jats:italic>B. burgdorferi<\/jats:italic>increases the production of adrenomedullin, which in turn negatively regulates the<jats:italic>B. burgdorferi-<\/jats:italic>stimulated inflammatory response.<\/jats:p>","DOI":"10.1128\/iai.00630-10","type":"journal-article","created":{"date-parts":[[2010,10,5]],"date-time":"2010-10-05T03:20:04Z","timestamp":1286248804000},"page":"5307-5313","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Role of Adrenomedullin in Lyme Disease"],"prefix":"10.1128","volume":"78","author":[{"given":"Meghan L.","family":"Marre","sequence":"first","affiliation":[{"name":"Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, 155 Harrison Avenue, Boston, Massachusetts 02111"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Courtney T.","family":"Darcy","sequence":"additional","affiliation":[{"name":"Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janeth","family":"Yinh","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shizuo","family":"Akira","sequence":"additional","affiliation":[{"name":"Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Uematsu","sequence":"additional","affiliation":[{"name":"Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allen C.","family":"Steere","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02111"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linden T.","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00314.2004"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2005.09.003"},{"key":"e_1_3_2_4_2","first-page":"546","volume":"10","year":"2003","unstructured":"Allaker, R. 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