title: Paired immunoglobulin-like receptor B (PIR-B) negatively regulates macrophage activation in experimental colitis.
abstract: OBJECTIVE
  Innate and adaptive immune responses are regulated by cross talk between activation and inhibitory signals. Dysregulation of the inhibitory signal can lead to aberrant chronic inflammatory diseases such as the inflammatory bowel diseases (IBD). Little is known about negative regulation of innate intestinal immune activation. We examined the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of macrophage function in innate intestinal immunity.
  
  
  METHODS
  We examined the susceptibility of Pirb-/- and wild-type (WT) mice to dextran sodium sulfate (DSS)-induced colitis. We assessed proinflammatory cytokine release and mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) activation in Pirb-/- and WT macrophages following Escherichia coli stimulation. Macrophage transfer experiments were performed to define the role of PIR-B in the negative regulation of macrophage function in DSS-induced colitis. We also assessed expression of PIR-B human homologues (immunoglobulin-like transcript [ILT]-2 and ILT-3) in colon biopsy samples from healthy individuals (controls) and patients with IBD.
  
  
  RESULTS
  Pirb-/- mice had increased susceptibility to DSS-induced colitis. In vitro analysis showed increased production of proinflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor alpha) and activation of MAPK and NF-kappaB in Pirb-/- macrophages following bacterial activation. Adoptive transfer of bone marrow-derived Pirb-/- macrophages into WT mice was sufficient to increase disease susceptibility. ILT-2 and ILT-3 were expressed on CD68+ and CD68- mononuclear cells and intestinal epithelium in colon biopsy samples from patients and controls.
  
  
  CONCLUSIONS
  PIR-B negatively regulates macrophage functions in response to pathogenic bacteria and chronic intestinal inflammatory responses. Inhibitory receptors such as PIR-B might be used as therapeutic targets for treatment of patients with IBD.
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Munitz
authors.forename: Eric T
authors.initials: ET
authors.lastname: Cole
authors.forename: Amanda
authors.initials: A
authors.lastname: Beichler
authors.forename: Katherine
authors.initials: K
authors.lastname: Groschwitz
authors.forename: Richard
authors.initials: R
authors.lastname: Ahrens
authors.forename: Kris
authors.initials: K
authors.lastname: Steinbrecher
authors.forename: Tara
authors.initials: T
authors.lastname: Willson
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.forename: Lee
authors.initials: L
authors.lastname: Denson
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
mesh_terms: D000293:Adolescent; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001706:Biopsy; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000472:pathogenicity; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000637:transplantation; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000032:analysis; D011971:Receptors, Immunologic / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D018836:Inflammation Mediators; C105299:LILRB1 protein, human; C107907:LILRB4 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C105949:Pirb protein, mouse; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D016264:Dextran Sulfate; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse
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