title: Toxoplasma gondii-derived heat shock protein 70 induces lethal anaphylactic reaction through activation of cytosolic phospholipase A2 and platelet-activating factor via Toll-like receptor 4/myeloid differentiation factor 88.
abstract: Toxoplasma gondii-derived heat shock protein 70 (T.g.HSP70) was proven to induce IFN-gamma-dependent lethal anaphylactic reaction in T. gondii-infected mice through an alternative PAF-mediated pathway, but not the classical immunoglobulin (Ig)E-dependent pathway. Although marked IFN-gamma production was observed by CD11b(+), CD11c(+), CD4(+) and CD8(+) splenocytes, CD11b(+) and CD11c(+) cells were shown to be the key effecter cells which generated pro-inflammatory lipid such as PAF and caused T.g.HSP70-induced anaphylactic reaction. In the present study, we found that the T.g.HSP70-induced anaphylactic reaction was not observed in TLR 4-deficient ((-/-)) mice, whereas it was observed in WT and TLR2(-/-) mice. The mRNA expression of PAF-AH, the main enzyme for PAF degradation, increased in T. gondii-infected WT and TLR2(-/-) but not in TLR4(-/-) mice after T.g.HSP70 injection. Furthermore, phosphorylation of cPLA(2), which is the key enzyme for pro-inflammatory lipid generation, was detected in CD11b(+) splenocytes of WT and TLR2(-/-) mice but not in TLR4(-/-) mice. Subsequently, cPLA(2) activation was suppressed by inhibiting the TLR4-directed p38 and p44/42 MAPK pathways. However, T.g.HSP70-induced anaphylactic reaction was observed in TRIF(-/-) mice, but not in MyD88(-/-) mice. These findings indicate the cPLA(2) activated-PAF production via TLR4/MyD88-dependent, but not TRIF-dependent, signaling pathway in T.g.HSP70-induced anaphylactic reaction in T. gondii-infected mice.
authors.affiliation: Department of Infection and Host Defense, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
authors.forename: Hye-Seong
authors.initials: HS
authors.lastname: Mun
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Kikumura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sayama
authors.forename: Kazumi
authors.initials: K
authors.lastname: Norose
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yano
authors.forename: Fumie
authors.initials: F
authors.lastname: Aosai
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000276:immunology; D000707:Anaphylaxis; D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology*; D054467:Phospholipases A2 / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000378:metabolism*; D015800:Protozoan Proteins / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology*; D014122:Toxoplasma / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D039481:CD11b Antigen; D018840:HSP70 Heat-Shock Proteins; D053594:Myeloid Differentiation Factor 88; D054467:Phospholipases A2; D010972:Platelet Activating Factor; D015800:Protozoan Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse