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Several studies have investigated inhibition of downstream mediators, including tumor necrosis factor alpha (TNF-\u03b1) and interleukin-1\u03b2 (IL-1\u03b2). Emerging evidence indicates that upstream inhibition is a better therapeutic approach for attenuating damaging immune activation. Therefore, we investigated inhibition of two central innate immune pathways, those of complement and CD14\/Toll-like receptor 4 (TLR4)\/myeloid differentiation protein 2 (MD-2), in a porcine in vitro model of<jats:italic>Escherichia coli<\/jats:italic>-induced inflammation. Porcine whole blood anticoagulated with lepuridin, which did not interfere with the complement system, was incubated with<jats:italic>E. coli<\/jats:italic>lipopolysaccharide (LPS) or whole bacteria. Inhibitors of complement and CD14 and thus the LPS CD14\/TLR4\/MD-2 receptor complex were tested to investigate the effect on the inflammatory response. A broad range of inflammatory readouts were used to monitor the effect. Anti-CD14 was found to saturate the CD14 molecule on granulocytes and completely inhibited LPS-induced proinflammatory cytokines in a dose-dependent manner. Anti-CD14 significantly reduced the levels of the<jats:italic>E. coli<\/jats:italic>-induced proinflammatory cytokines TNF-\u03b1 and IL-1\u03b2, but not IL-8, in a dose-dependent manner. No effect on bacterial clearance was seen. Vaccinia complement control protein and smallpox inhibitor of complement enzymes, two<jats:italic>Orthopoxvirus<\/jats:italic>-encoded complement inhibitors, completely inhibited complement activation. Furthermore, these agents almost completely inhibited the expression of wCD11R3, which is associated with CD18 as a \u03b22 integrin, on porcine granulocytes and decreased IL-8 levels significantly in a dose-dependent manner. As expected, complement inhibition reduced bacterial clearance. We conclude that inhibition of complement and CD14 attenuates<jats:italic>E. coli<\/jats:italic>-induced inflammation and might be used as a therapeutic regimen in gram-negative sepsis along with appropriate treatment with antibiotics.<\/jats:p>","DOI":"10.1128\/iai.01305-08","type":"journal-article","created":{"date-parts":[[2008,12,2]],"date-time":"2008-12-02T01:59:42Z","timestamp":1228183182000},"page":"725-732","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":32,"title":["Inhibition of Complement and CD14 Attenuates the<i>Escherichia coli<\/i>-Induced Inflammatory Response in Porcine Whole Blood"],"prefix":"10.1128","volume":"77","author":[{"given":"Ebbe Billmann","family":"Thorgersen","sequence":"first","affiliation":[{"name":"Institute of Immunology, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Pharo","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Haverson","sequence":"additional","affiliation":[{"name":"Department of Clinical Veterinary Science, University of Bristol, Bristol BS40 5DU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne K.","family":"Axelsen","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Gaustad","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girish J.","family":"Kotwal","sequence":"additional","affiliation":[{"name":"Division of Medical Virology, IIDMM, University of Cape Town, HSC, Cape Town 7925, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Sfyroera","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom Eirik","family":"Mollnes","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.02.015"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200405000-00002"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod63.3.858"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1085536"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0806538"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.16.10689"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01326"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-2427(01)00286-0"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.76.060305.151318"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1352.024"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(00)00149-2"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(94)90398-0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.2.618"},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.4049\/jimmunol.162.7.3749","volume":"162","year":"1999","unstructured":"Hoshino, K., O. 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