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Platelet-activating factor-mediated NF-kappaB dependency of a late anaphylactic reaction.

Choi IW, Kim YS, Kim DK, Choi JH, Seo KH, Im SY, Kwon KS, Lee MS, Ha TY, Lee HK - J. Exp. Med. (2003)

Bottom Line: Using a murine model of penicillin V-induced systemic anaphylaxis, we show an autoregulatory cascade of biphasic anaphylactic reactions.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, University National Medical School, Chonju, Chonbuk, 561-182, South Korea.

ABSTRACT
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.

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Involvement of TNF-α in the development of the late anaphylactic reactions. (a) Time course of serum levels of TNF-α (○) and IL-1 (▵) during anaphylaxis. (b) TNF-α inhibition by pretreatment with CV 6209 (▵) and PDTC (□). ○, control group. (c and d) Inhibition of the late phase increase in plasma PAF (c) and hematocrit value (d) by anti–TNF-α Ab (▪). □, control Ab. Abs were injected i.p. 45 min after challenge injection. Blood was collected 7.5 h after the challenge. (e) Serum levels of Pen V–specific IgE. Blood samples were taken 1 d before challenge. (f) No late phase increase in plasma PAF and hematocrit value in TNF-α2/2 mice (▵). ○, control littermates. Blood was collected 7.5 h after the challenge. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 4 for each time point). **, P < 0.05; *, P < 0.01 versus control; Mann-Whitney U test.
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fig3: Involvement of TNF-α in the development of the late anaphylactic reactions. (a) Time course of serum levels of TNF-α (○) and IL-1 (▵) during anaphylaxis. (b) TNF-α inhibition by pretreatment with CV 6209 (▵) and PDTC (□). ○, control group. (c and d) Inhibition of the late phase increase in plasma PAF (c) and hematocrit value (d) by anti–TNF-α Ab (▪). □, control Ab. Abs were injected i.p. 45 min after challenge injection. Blood was collected 7.5 h after the challenge. (e) Serum levels of Pen V–specific IgE. Blood samples were taken 1 d before challenge. (f) No late phase increase in plasma PAF and hematocrit value in TNF-α2/2 mice (▵). ○, control littermates. Blood was collected 7.5 h after the challenge. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 4 for each time point). **, P < 0.05; *, P < 0.01 versus control; Mann-Whitney U test.

Mentions: The activation of NF-κB results in the expression of proinflammatory cytokine genes, such as TNF-α and IL-1 (13, 14). Therefore, we investigated whether TNF-α and IL-1 are produced in an NF-κB–dependent manner during anaphylaxis. Serum TNF-α levels peaked 1–1.5 h after challenge (Fig. 3 a) and declined rapidly thereafter. In contrast, IL-1 was not detected in the circulation during the observation period. The administration of a PAF antagonist and an NF-κB inhibitor nearly completely inhibited the increase in serum TNF-α levels after the challenge (Fig. 3 b), indicating that production of TNF-α during anaphylaxis is a PAF-induced NF-κB–dependent process.


Platelet-activating factor-mediated NF-kappaB dependency of a late anaphylactic reaction.

Choi IW, Kim YS, Kim DK, Choi JH, Seo KH, Im SY, Kwon KS, Lee MS, Ha TY, Lee HK - J. Exp. Med. (2003)

Involvement of TNF-α in the development of the late anaphylactic reactions. (a) Time course of serum levels of TNF-α (○) and IL-1 (▵) during anaphylaxis. (b) TNF-α inhibition by pretreatment with CV 6209 (▵) and PDTC (□). ○, control group. (c and d) Inhibition of the late phase increase in plasma PAF (c) and hematocrit value (d) by anti–TNF-α Ab (▪). □, control Ab. Abs were injected i.p. 45 min after challenge injection. Blood was collected 7.5 h after the challenge. (e) Serum levels of Pen V–specific IgE. Blood samples were taken 1 d before challenge. (f) No late phase increase in plasma PAF and hematocrit value in TNF-α2/2 mice (▵). ○, control littermates. Blood was collected 7.5 h after the challenge. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 4 for each time point). **, P < 0.05; *, P < 0.01 versus control; Mann-Whitney U test.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196087&req=5

fig3: Involvement of TNF-α in the development of the late anaphylactic reactions. (a) Time course of serum levels of TNF-α (○) and IL-1 (▵) during anaphylaxis. (b) TNF-α inhibition by pretreatment with CV 6209 (▵) and PDTC (□). ○, control group. (c and d) Inhibition of the late phase increase in plasma PAF (c) and hematocrit value (d) by anti–TNF-α Ab (▪). □, control Ab. Abs were injected i.p. 45 min after challenge injection. Blood was collected 7.5 h after the challenge. (e) Serum levels of Pen V–specific IgE. Blood samples were taken 1 d before challenge. (f) No late phase increase in plasma PAF and hematocrit value in TNF-α2/2 mice (▵). ○, control littermates. Blood was collected 7.5 h after the challenge. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 4 for each time point). **, P < 0.05; *, P < 0.01 versus control; Mann-Whitney U test.
Mentions: The activation of NF-κB results in the expression of proinflammatory cytokine genes, such as TNF-α and IL-1 (13, 14). Therefore, we investigated whether TNF-α and IL-1 are produced in an NF-κB–dependent manner during anaphylaxis. Serum TNF-α levels peaked 1–1.5 h after challenge (Fig. 3 a) and declined rapidly thereafter. In contrast, IL-1 was not detected in the circulation during the observation period. The administration of a PAF antagonist and an NF-κB inhibitor nearly completely inhibited the increase in serum TNF-α levels after the challenge (Fig. 3 b), indicating that production of TNF-α during anaphylaxis is a PAF-induced NF-κB–dependent process.

Bottom Line: Using a murine model of penicillin V-induced systemic anaphylaxis, we show an autoregulatory cascade of biphasic anaphylactic reactions.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, University National Medical School, Chonju, Chonbuk, 561-182, South Korea.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus