title: Heme mediated STAT3 activation in severe malaria.
abstract: BACKGROUND
  The mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated.
  
  
  METHODS
  We first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line.
  
  
  RESULTS
  The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling.
  
  
  CONCLUSIONS
  Our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria.
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Mingli
authors.initials: M
authors.lastname: Liu
authors.forename: Audu S
authors.initials: AS
authors.lastname: Amodu
authors.forename: Sidney
authors.initials: S
authors.lastname: Pitts
authors.forename: John
authors.initials: J
authors.lastname: Patrickson
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Hibbert
authors.forename: Monica
authors.initials: M
authors.lastname: Battle
authors.forename: Solomon F
authors.initials: SF
authors.lastname: Ofori-Acquah
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Stiles
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D054357:Chemokine CXCL10 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006418:Heme / Q000737:chemistry*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000473:pathology; D008168:Lung / Q000473:pathology; D008288:Malaria / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010962:Plasmodium berghei / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D054357:Chemokine CXCL10; D018925:Chemokines; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D008565:Membrane Proteins; D054367:Receptors, CXCR3; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D006418:Heme; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse