title: Deletion of LTbetaR augments male susceptibility to Plasmodium chabaudi.
abstract: SUMMARY Disruption of the lymphotoxin beta receptor (LTbetaR) gene has been shown to result in enhanced resistance of female mice to blood-stage Plasmodium chabaudi malaria. Here, we investigate the effect of LTbetaR deletion on host defence of males. In contrast to females, male LTbetaR(-/-) mice do not exhibit any increase in resistance. Conversely, they are even more susceptible than wild-type C57BL/6 mice, which becomes evident after lowering circulating levels of testosterone by castration, which makes C57BL/6 males resistant, whereas LTbetaR(-/-) remain susceptible. Gene-expression analysis using cDNA arrays revealed no differences in immunological responses in spleen of malaria-resistant female and malaria-susceptible castrated male LTbetaR(-/-) mice. In the liver, however, expression levels of plasminogen activator inhibitor PAI1, chemokine CXCL10, dual specificity phosphatase DUSP1, and hydroxysteroid-specific sulfotransferases Sult2a1/2 were decreased 6- to 85-fold in susceptible castrated male LTbetaR(-/-) mice in comparison to resistant female LTbetaR(-/-) mice at maximal parasitaemia, as evidenced by Northern blot analyses. The present data support our previous view that the liver is involved in the combat against malarial blood stages and that down-regulation of the genes DUSP1 and Sult2a1/2 signals dysregulation of protective liver responses, thus possibly contributing to male susceptibility of LTbetaR(-/-) mice.
authors.affiliation: Division of Molecular Parasitology and Biological and Medical Research Centre, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Krücken
authors.forename: J V
authors.initials: JV
authors.lastname: Braun
authors.forename: M A
authors.initials: MA
authors.lastname: Dkhil
authors.forename: A
authors.initials: A
authors.lastname: Grunwald
authors.forename: F
authors.initials: F
authors.lastname: Wunderlich
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics; D054638:Dual Specificity Phosphatase 1; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D017874:Immediate-Early Proteins / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000502:physiology; D053259:Lymphotoxin beta Receptor; D008288:Malaria / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009919:Orchiectomy; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D016788:Plasmodium chabaudi / Q000276:immunology*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology*; D012737:Sex Factors; D013154:Spleen / Q000378:metabolism / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D017874:Immediate-Early Proteins; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases