title: Regulation of Pseudomonas aeruginosa corneal infection in IL-1 beta converting enzyme (ICE, caspase-1) deficient mice.
abstract: OBJECTIVE
  Antibody neutralization studies have shown that in Pseudomonas aeruginosa corneal infection, IL-1 beta is critical to regulation of the host inflammatory response, but mechanisms remain undetermined. To elucidate these mechanisms, caspase-1 knockout (ICE(-/-)) mice, that do not release mature IL-1 beta after endotoxin challenge, were tested.
  
  
  METHODS
  Clinical scores, MPO activity (for PMN quantitation), bacterial plate count, semiquantitative RT-PCR, ELISA and TUNEL staining were used to characterize the inflammatory response after infection in knockout and C57BL/6 (B6) wild type mice.
  
  
  RESULTS
  Clinical scores were significantly reduced in ICE(-/-) vs. B6 mice at 3, 5 and 7 days postinfection (p.i.). The decreased inflammatory response of ICE(-/-) mice was striking at 1 day p.i., and bacterial load also was significantly reduced in the cornea of the knockout mice at 3-7 days p.i. Knockout mice exhibited significantly increased mRNA and protein levels for IL-1Ra, the physiological regulator of IL-1 activity, and in addition, a significant increase in the number of apoptotic cells were quantitated in the corneal epithelium of ICE(-/-) vs. B6 mice at 1 day p.i.
  
  
  CONCLUSIONS
  These data provide evidence that bacterial infection in the cornea of ICE(-/-) mice induces a reduced inflammatory response by: reduction in PMN and cytokines and chemokines that attract these cells to the cornea; enhanced apoptotic cell death in the infected epithelium; and increased IL-1Ra levels. The data also confirm the importance of IL-1 regulation in this model and suggest that ICE inhibition may be an attractive ancillary therapeutic strategy to control the host response to this pathogen.
authors.affiliation: Department of Anatomy & Cell Biology, Wayne State University School of Medicine, Detroit, MI 4820, USA. athakur@med.wayne.edu
authors.forename: Archana
authors.initials: A
authors.lastname: Thakur
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Barrett
authors.forename: Sharon
authors.initials: S
authors.lastname: McClellan
authors.forename: Linda D
authors.initials: LD
authors.lastname: Hazlett
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000172:deficiency* / Q000235:genetics; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D015169:Colony Count, Microbial; D003320:Corneal Ulcer / Q000201:enzymology / Q000382:microbiology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D015818:Eye Infections, Bacterial / Q000201:enzymology / Q000382:microbiology* / Q000473:pathology; D005260:Female; D020287:In Situ Nick-End Labeling; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D011552:Pseudomonas Infections / Q000201:enzymology / Q000382:microbiology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D009195:Peroxidase; D020170:Caspase 1