title: Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism.
abstract: Malaria, caused by infection with Plasmodium spp., is a life cycle-specific disease that includes liver injury at the erythrocyte stage of the parasite. In this study, we have investigated the mechanisms underlying Plasmodium berghei-induced liver injury, which is characterized by the presence of apoptotic and necrotic hepatocytes and dense infiltration of lymphocytes. Although both IL-12 and IL-18 serum levels were elevated after infection, IL-12-deficient, but not IL-18-deficient, mice were resistant to liver injury induced by P. berghei. Neither elevation of serum IL-12 levels nor liver injury was observed in mice deficient in myeloid differentiation factor 88 (MyD88), an adaptor molecule shared by Toll-like receptors (TLRs). These results demonstrated a requirement of the TLR-MyD88 pathway for induction of IL-12 production during P. berghei infection. Hepatic lymphocytes from P. berghei-infected wild-type mice lysed hepatocytes from both uninfected and infected mice. The hepatocytotoxic action of these cells was blocked by a perforin inhibitor but not by a neutralizing anti-Fas ligand Ab and was up-regulated by IL-12. Surprisingly, these cells killed hepatocytes in an MHC-unrestricted manner. However, CD1d-deficient mice that lack CD1d-restricted NK T cells, were susceptible to liver injury induced by P. berghei. Collectively, our results indicate that the liver injury induced by P. berghei infection of mice induces activation of the TLR-MyD88 signaling pathway which results in IL-12 production and activation of the perforin-dependent cytotoxic activities of MHC-unrestricted hepatic lymphocytes.
authors.affiliation: Department of Immunology and Medical Zoology, Institute for Advanced Medical Science, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Adachi
authors.forename: H
authors.initials: H
authors.lastname: Tsutsui
authors.forename: S
authors.initials: S
authors.lastname: Kashiwamura
authors.forename: E
authors.initials: E
authors.lastname: Seki
authors.forename: H
authors.initials: H
authors.lastname: Nakano
authors.forename: O
authors.initials: O
authors.lastname: Takeuchi
authors.forename: K
authors.initials: K
authors.lastname: Takeda
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: L
authors.initials: L
authors.lastname: Van Kaer
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: K
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018949:Antigens, CD1 / Q000032:analysis; D055610:Antigens, CD1d; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D003601:Cytotoxicity Tests, Immunologic; D029721:Drosophila Proteins; D053222:Fas Ligand Protein; D005260:Female; D006520:Hepatitis, Animal / Q000209:etiology / Q000469:parasitology* / Q000473:pathology; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D020382:Interleukin-18 / Q000235:genetics / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000473:pathology; D008288:Malaria / Q000209:etiology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D054353:Perforin; D010962:Plasmodium berghei; D052899:Pore Forming Cytotoxic Proteins; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic; D016176:T-Lymphocyte Subsets / Q000276:immunology; D051193:Toll-Like Receptors; D019014:fas Receptor / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018949:Antigens, CD1; D055610:Antigens, CD1d; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D020382:Interleukin-18; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D052899:Pore Forming Cytotoxic Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D019014:fas Receptor; D054353:Perforin; D018664:Interleukin-12