caa a22 4500 445795948 CHVBK 20180317145125.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s10620-010-1396-x doi (NATIONALLICENCE)springer-10.1007/s10620-010-1396-x A Role for Intestinal Alkaline Phosphatase in the Maintenance of Local Gut Immunity [Elektronische Daten] [Kathryn Chen, Madhu Malo, Laura Beasley-Topliffe, Klaas Poelstra, Jose Millan, Golam Mostafa, Sayeda Alam, Sundaram Ramasamy, H. Warren, Elizabeth Hohmann, Richard Hodin] Background and Aims: Intestinal alkaline phosphatase (IAP) is a gut mucosal defense factor known to dephosphorylate lipopolysaccharide (LPS); however, the role of IAP in the gut response to luminal bacteria remains poorly defined. We investigated immune responses of wild-type (WT) and IAP-knockout (IAP-KO) mice to LPS and Salmonella typhimurium challenges. Methods: Cryostat sectioning and standard indirect immunohistochemical staining for major histocompatibility complex (MHC) classII molecules were performed on liver tissue from WT and IAP-KO mice. WT and IAP-KO mice were orally gavaged with S.typhimurium; bacterial translocation to mesenteric nodes, liver, and spleen was determined by tissue homogenization and plating. In other experiments, WT and IAP-KO mice received intraperitoneal injections of LPS, with subsequent quantification of complete blood counts and serum interleukin (IL)-6 by enzyme-linked immunosorbent assay (ELISA). WT and IAP-KO whole blood were plated and stimulated with LPS and Pam-3-Cys, followed by cytokine assays. Results: Immunohistologic liver examinations showed increased expression of MHC classII molecules in IAP-KO mice. Following S.typhimurium challenge, WT mice appeared moribund compared with IAP-KO mice, with increased bacterial translocation. WT mice had >50% decrease (P<.005) in platelets and 1.8-fold (P<.05) increased serum IL-6 compared with IAP-KO mice in response to LPS injections. IAP-KO whole-blood stimulation with LPS and Pam-3-Cys resulted in increased IL-6 and tumor necrosis factor (TNF)-alpha secretion compared with WT. Conclusions: IAP-KO mice exhibit characteristics consistent with local LPS tolerance. Whole-blood response of IAP-KO mice did not reflect systemic tolerance. These data suggest that IAP is a local immunomodulating factor, perhaps regulating LPS-toll-like receptor 4 (TLR4) interaction between commensal microflora and intestinal epithelium. Springer Science+Business Media, LLC, 2010 Mucosal gut defense factor nationallicence Lipopolysaccharide nationallicence Tolerance nationallicence TLR4 nationallicence Chen Kathryn Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Malo Madhu Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Beasley-Topliffe Laura Division of Infectious Disease, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Poelstra Klaas Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands aut Millan Jose Sanford Children's Health Research Center, Burnham Institute for Medical Research, 92037, La Jolla, CA, USA aut Mostafa Golam Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Alam Sayeda Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Ramasamy Sundaram Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Warren H. Division of Infectious Disease, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Hohmann Elizabeth Division of Infectious Disease, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Hodin Richard Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/4(2011-04-01), 1020-1027 0163-2116 56:4<1020 2011 56 10620 https://doi.org/10.1007/s10620-010-1396-x text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10620-010-1396-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Chen Kathryn Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Malo Madhu Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Beasley-Topliffe Laura Division of Infectious Disease, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Poelstra Klaas Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Millan Jose Sanford Children's Health Research Center, Burnham Institute for Medical Research, 92037, La Jolla, CA, USA aut NATIONALLICENCE 700 1- Mostafa Golam Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Alam Sayeda Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Ramasamy Sundaram Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Warren H. Division of Infectious Disease, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Hohmann Elizabeth Division of Infectious Disease, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Hodin Richard Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 773 0- Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/4(2011-04-01), 1020-1027 0163-2116 56:4<1020 2011 56 10620 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer