title: Ron receptor-dependent gene regulation of Kupffer cells during endotoxemia.
abstract: BACKGROUND
  Ron receptor tyrosine kinase signaling in macrophages, including Kupffer cells and alveolar macrophages, suppresses endotoxin-induced proinflammatory cytokine/chemokine production. Further, we have also identified genes from Ron replete and Ron deplete livers that were differentially expressed during the progression of liver inflammation associated with acute liver failure in mice by microarray analyses. While important genes and signaling pathways have been identified downstream of Ron signaling during progression of inflammation by this approach, the precise role that Ron receptor plays in regulating the transcriptional landscape in macrophages, and particular in isolated Kupffer cells, has still not been investigated.
  
  
  METHODS
  Kupffer cells were isolated from wild-type (TK+/+) and Ron tyrosine kinase deficient (TK-/-) mice. Ex vivo, the cells were treated with lipopolysaccharide (LPS) in the presence or absence of the Ron ligand, hepatocyte growth factor-like protein (HGFL). Microarray and qRT-PCR analyses were utilized to identify alterations in gene expression between genotypes.
  
  
  RESULTS
  Microarray analyses identified genes expressed differentially in TK+/+ and TK-/- Kupffer cells basally as well as after HGFL and LPS treatment. Interestingly, our studies identified Mefv, a gene that codes for the anti-inflammatory protein pyrin, as an HGFL-stimulated Ron-dependent gene. Moreover, lipocalin 2, a proinflammatory gene, which is induced by LPS, was significantly suppressed by HGFL treatment. Microarray results were validated by qRT-PCR studies on Kupffer cells treated with LPS and HGFL.
  
  
  CONCLUSIONS
  The studies herein suggest a novel mechanism whereby HGFL-induced Ron receptor activation promotes the expression of anti-inflammatory genes while inhibiting genes involved in inflammation with a net effect of diminished inflammation in macrophages.
authors.affiliation: Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45267-0521, USA. susan.waltz@uc.edu.
authors.forename: Rishikesh M
authors.initials: RM
authors.lastname: Kulkarni
authors.forename: William D
authors.initials: WD
authors.lastname: Stuart
authors.forename: Susan E
authors.initials: SE
authors.lastname: Waltz
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D019446:Endotoxemia / Q000201:enzymology* / Q000235:genetics; D004731:Endotoxins / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000201:enzymology*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D000071198:Pyrin; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000209:Acute-Phase Proteins; D003598:Cytoskeletal Proteins; D004731:Endotoxins; D018836:Inflammation Mediators; D000071068:Lipocalin-2; D054834:Lipocalins; C000604193:Mefv protein, mouse; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D000071198:Pyrin; C082332:macrophage stimulating protein; C071332:Lcn2 protein, mouse; D017228:Hepatocyte Growth Factor; C044101:endotoxin, Escherichia coli; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases