title: Plasmodium berghei ANKA infection increases Foxp3, IL-10 and IL-2 in CXCL-10 deficient C57BL/6 mice.
abstract: BACKGROUND
  Cerebral malaria (CM) is a major cause of malaria mortality. Sequestration of infected red blood cells and leukocytes in brain vessels coupled with the production of pro-inflammatory factors contribute to CM. CXCL-10 a chemokine that is chemotactic to T cells has been linked to fatal CM. Mice deficient for CXCL-10 gene are resistant to murine CM, while antibody ablation of CXCL-10 enhanced the production of regulatory T cells (CD4+Cd25+Foxp3+) and IL-10 which regulate the immune system. Interleukin-2 (IL-2), a pro-inflammatory cytokine implicated in malaria pathogenesis has also been shown to be a key regulator of Foxp3. However the role of Foxp3 in resistant murine CM is not well understood.
  
  
  METHODS
  The hypothesis that resistance of CXCL-10-/- mice to murine CM may be due to enhanced expression of Foxp3 in concert with IL-10 and IL-2 was tested. CXCL-10-/- and WT C57BL/6 mice were infected with Plasmodium berghei ANKA and evaluated for CM symptoms. Brain, peripheral blood mononuclear cells (PBMCs) and plasma were harvested from infected and uninfected mice at days 2, 4 and 8. Regulatory T cells (CD4+CD25+) and non-T regs (CD4+CD25-) were isolated from PBMCs and cultured with P. berghei antigens in vitro with dendritic cells as antigen presenting cells. Regulatory T cell transcription and specific factor Foxp3, was evaluated in mouse brain and PBMCs by realtime-PCR and Western blots while IL-10, and IL-2 were evaluated in plasma and cultured supernatants by ELISA.
  
  
  RESULTS
  Wild type mice exhibited severe murine CM symptoms compared with CXCL-10-/- mice. Foxp3 mRNA and protein in brain and PBMC's of CXCL-10-/- mice was significantly up-regulated (p < 0.05) by day 4 post-infection (p.i) compared with WT. Plasma levels of IL-10 and IL-2 in infected CXCL-10-/- were higher than in WT mice (p < 0.05) at days 2 and 4 p.i. Ex-vivo CD4+CD25+ T cells from CXCL-10-/- re-stimulated with P. berghei antigens produced more IL-10 than WT CD4+CD25+ T cells.
  
  
  CONCLUSIONS
  The results indicate that in the absence of CXCL-10, the resulting up-regulation of Foxp3, IL-10 and IL-2 may be involved in attenuating fatal murine CM.
authors: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Drive, South West, Atlanta Georgia, GA 30310, USA.
authors: Bismark Y
authors: BY
authors: Sarfo
authors: Nana O
authors: NO
authors: Wilson
authors: Vincent C
authors: VC
authors: Bond
authors: Jonathan K
authors: JK
authors: Stiles
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000276:immunology / Q000469:parasitology; D015704:CD4 Antigens / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000276:immunology*; D016133:Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D015704:CD4 Antigens; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D007376:Interleukin-2; D016753:Interleukin-10