Platelet-activating factor-mediated NF-kappaB dependency of a late anaphylactic reaction.
Anaphylaxis is a life-threatening systemic allergic reaction with the potential for a recurrent or biphasic pattern. Despite an incidence of biphasic reaction between 5 and 20%, the molecular mechanism for the reaction is unknown. Using a murine model of penicillin V-induced systemic anaphylaxis, we show an autoregulatory cascade of biphasic anaphylactic reactions. Induction of anaphylaxis caused a rapid increase in circulating platelet-activating factor (PAF) levels. In turn, the elevated PAF contributes to the early phase of anaphylaxis as well as the subsequent activation of the nuclear factor (NF)-kappaB, a crucial transcription factor regulating the expression of many proinflammatory cytokines and immunoregulatory molecules. The induction of NF-kappaB activity is accompanied by TNF-alpha production, which, in turn, promotes late phase PAF synthesis. This secondary wave of PAF production leads eventually to the late phase of anaphylactic reactions. Mast cells do not appear to be required for development of the late phase anaphylaxis. Together, this work reveals the first mechanistic basis for biphasic anaphylactic reactions and provides possible therapeutic strategies for human anaphylaxis.
Choi
Il-Whan
IW
Department of Immunology, University National Medical School, Chonju, Chonbuk, 561-182, South Korea.
Kim
Young-Suk
YS
Kim
Dae-Ki
DK
Choi
Jung-Hwa
JH
Seo
Kook-Heon
KH
Im
Shun-Young
SY
Kwon
Keun-Sang
KS
Lee
Myung-Shik
MS
Ha
Tai-You
TY
Lee
Hern-Ku
HK
D000707:Anaphylaxis / Q000209:etiology*; D000818:Animals; D006400:Hematocrit; D007375:Interleukin-1 / Q000235:genetics; D008297:Male; D008407:Mast Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D010741:Phospholipases A / Q000378:metabolism; D010972:Platelet Activating Factor / Q000032:analysis / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007375:Interleukin-1; D016328:NF-kappa B; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D010741:Phospholipases A