title: Regulation of chemokines, CCL3 and CCL4, by interferon γ and nitric oxide synthase 2 in mouse macrophages and during Salmonella enterica serovar typhimurium infection.
abstract: BACKGROUND
  Interferon γ (IFN-γ) increases the expression of multiple genes and responses; however, the mechanisms by which IFN-γ downmodulates cellular responses is not well understood. In this study, the repression of CCL3 and CCL4 by IFN-γ and nitric oxide synthase 2 (NOS2) in macrophages and upon Salmonella typhimurium infection of mice was investigated.
  
  
  METHODS
  Small molecule regulators and adherent peritoneal exudates cells (A-PECs) from Nos2(-/-)mice were used to identify the contribution of signaling molecules during IFN-γ-mediated in vitro regulation of CCL3, CCL4, and CXCL10. In addition, infection of bone marrow-derived macrophages (BMDMs) and mice (C57BL/6, Ifn-γ(-/), and Nos2(-/-)) with S. typhimurium were used to gain an understanding of the in vivo regulation of these chemokines.
  
  
  RESULTS
  IFN-γ repressed CCL3 and CCL4 in a signal transducer and activator of transcription 1 (STAT1)-NOS2-p38 mitogen activated protein kinase (p38MAPK)-activating transcription factor 3 (ATF3) dependent pathway in A-PECs. Also, during intracellular replication of S. typhimurium in BMDMs, IFN-γ and NOS2 repressed CCL3 and CCL4 production. The physiological roles of these observations were revealed during oral infection of mice with S. typhimurium, wherein endogenous IFN-γ and NOS2 enhanced serum amounts of tumor necrosis factor α and CXCL10 but repressed CCL3 and CCL4.
  
  
  CONCLUSIONS
  This study sheds novel mechanistic insight on the regulation of CCL3 and CCL4 in mouse macrophages and during S. typhimurium oral infection.
authors: Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India.
authors: Bhagawat
authors: B
authors: Chandrasekar
authors: Mukta
authors: M
authors: Deobagkar-Lele
authors: Emmanuel S
authors: ES
authors: Victor
authors: Dipankar
authors: D
authors: Nandi
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism*; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism*; D054357:Chemokine CXCL10; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012486:Salmonella typhimurium / Q000378:metabolism / Q000472:pathogenicity; D013234:Stem Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases