Immunoglobulin-Like Receptor B ( PIR-B ) Negatively Regulates acrophage Activation in Experimental Colitis

e r u m r a g r W ACKGROUND & AIMS: Innate and adaptive immune esponses are regulated by cross talk between activation nd inhibitory signals. Dysregulation of the inhibitory ignal can lead to aberrant chronic inflammatory diseases uch as the inflammatory bowel diseases (IBD). Little is nown about negative regulation of innate intestinal mmune activation. We examined the role of the inhibiory receptor paired immunoglobulin-like receptor B PIR-B) in the regulation of macrophage function in nnate intestinal immunity. METHODS: We examined he susceptibility of Pirb / and wild-type (WT) mice to extran sodium sulfate (DSS)-induced colitis. We assessed roinflammatory cytokine release and mitogen-activated rotein kinase (MAPK) and nuclear factor B (NFB) acivation in Pirb / and WT macrophages following Escheichia coli stimulation. Macrophage transfer experiments ere performed to define the role of PIR-B in the negative egulation of macrophage function in DSS-induced colitis. e also assessed expression of PIR-B human homologues immunoglobulin-like transcript [ILT]-2 and ILT-3) in coon biopsy samples from healthy individuals (controls) and atients with IBD. RESULTS: Pirb / mice had increased usceptibility to DSS-induced colitis. In vitro analysis howed increased production of proinflammatory cytokines interleukin-6, interleukin-1 , and tumor necrosis factor ) nd activation of MAPK and NFB in Pirb / macrophages ollowing bacterial activation. Adoptive transfer of bone arrow–derived Pirb / macrophages into WT mice was ufficient to increase disease susceptibility. ILT-2 and ILT-3 ere expressed on CD68 and CD68 mononuclear cells nd intestinal epithelium in colon biopsy samples from atients and controls. CONCLUSIONS: PIR-B negatively egulates macrophage functions in response to pathoenic bacteria and chronic intestinal inflammatory reponses. Inhibitory receptors such as PIR-B might be sed as therapeutic targets for treatment of patients ith IBD.