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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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Mast cells are not involved in the late phase of anaphylaxis. (a) Time course of plasma histamine levels after challenge in C57BL/6 mice. (b) The late phase increase in plasma PAF and hematocrit value in W/Wv mice. Blood was collected 7.5 h after challenge injection. (c) Comparison of serum levels of TNF-α between +/+ and W/Wv mice during anaphylaxis. Blood was collected 80 min after challenge injection. (d) Inhibition of the second phase of increase in hematocrit value by anti–TNF-α Ab. 2 mg/mouse Ab was injected i.p. 45 min after challenge injection. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 3 for each time point). P < 0.01 versus control; Mann-Whitney U test.
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fig5: Mast cells are not involved in the late phase of anaphylaxis. (a) Time course of plasma histamine levels after challenge in C57BL/6 mice. (b) The late phase increase in plasma PAF and hematocrit value in W/Wv mice. Blood was collected 7.5 h after challenge injection. (c) Comparison of serum levels of TNF-α between +/+ and W/Wv mice during anaphylaxis. Blood was collected 80 min after challenge injection. (d) Inhibition of the second phase of increase in hematocrit value by anti–TNF-α Ab. 2 mg/mouse Ab was injected i.p. 45 min after challenge injection. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 3 for each time point). P < 0.01 versus control; Mann-Whitney U test.

Mentions: To investigate a role for mast cells in the development of the late anaphylactic reactions, we determined the time course of plasma histamine levels after the challenge and examined whether the late anaphylactic reaction occurs in mast cell–deficient WBB6F1-W/Wv (W/Wv) mice. Levels of circulating histamine reached a peak within 10 min, but rapidly declined thereafter and remained within the basal level during the observation period (Fig. 5 a). The late anaphylactic reactions such as increases in plasma PAF concentration and hemoconcentration developed to a similar degree in both mast cell–sufficient control +/+ and W/Wv mice (Fig. 5 b). From these data, mast cells do not appear to be required for development of the late anaphylactic reaction. Because mast cells are one source of both the cytokines TNF-α and IL-1 (25), we examined the circulating TNF-α levels during anaphylaxis in W/Wv mice. W/Wv mice were defective in producing TNF-α as W/Wv mice possess 20–30% of the wild-type level (Fig. 5 c). Circulating IL-1β was not detected in W/Wv mice during anaphylaxis (unpublished data). This reduced level of TNF-α in W/Wv mice seems to be due to the lower level of circulating PAF during anaphylaxis (18) and the absence of mast cell–derived TNF-α. Pretreatment with anti–TNF-α resulted in abrogation of the late increase in hematocrit in both wild-type and W/Wvmice (Fig. 5 d). Therefore, it is likely that TNF-α is also a key cytokine in the development of a late anaphylactic reaction in W/Wv, even with a reduced capacity to produce this cytokine.


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)

Mast cells are not involved in the late phase of anaphylaxis. (a) Time course of plasma histamine levels after challenge in C57BL/6 mice. (b) The late phase increase in plasma PAF and hematocrit value in W/Wv mice. Blood was collected 7.5 h after challenge injection. (c) Comparison of serum levels of TNF-α between +/+ and W/Wv mice during anaphylaxis. Blood was collected 80 min after challenge injection. (d) Inhibition of the second phase of increase in hematocrit value by anti–TNF-α Ab. 2 mg/mouse Ab was injected i.p. 45 min after challenge injection. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 3 for each time point). P < 0.01 versus control; Mann-Whitney U test.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196087&req=5

fig5: Mast cells are not involved in the late phase of anaphylaxis. (a) Time course of plasma histamine levels after challenge in C57BL/6 mice. (b) The late phase increase in plasma PAF and hematocrit value in W/Wv mice. Blood was collected 7.5 h after challenge injection. (c) Comparison of serum levels of TNF-α between +/+ and W/Wv mice during anaphylaxis. Blood was collected 80 min after challenge injection. (d) Inhibition of the second phase of increase in hematocrit value by anti–TNF-α Ab. 2 mg/mouse Ab was injected i.p. 45 min after challenge injection. Results for all panels are expressed as the mean ± SEM of three separate experiments (n = 3 for each time point). P < 0.01 versus control; Mann-Whitney U test.
Mentions: To investigate a role for mast cells in the development of the late anaphylactic reactions, we determined the time course of plasma histamine levels after the challenge and examined whether the late anaphylactic reaction occurs in mast cell–deficient WBB6F1-W/Wv (W/Wv) mice. Levels of circulating histamine reached a peak within 10 min, but rapidly declined thereafter and remained within the basal level during the observation period (Fig. 5 a). The late anaphylactic reactions such as increases in plasma PAF concentration and hemoconcentration developed to a similar degree in both mast cell–sufficient control +/+ and W/Wv mice (Fig. 5 b). From these data, mast cells do not appear to be required for development of the late anaphylactic reaction. Because mast cells are one source of both the cytokines TNF-α and IL-1 (25), we examined the circulating TNF-α levels during anaphylaxis in W/Wv mice. W/Wv mice were defective in producing TNF-α as W/Wv mice possess 20–30% of the wild-type level (Fig. 5 c). Circulating IL-1β was not detected in W/Wv mice during anaphylaxis (unpublished data). This reduced level of TNF-α in W/Wv mice seems to be due to the lower level of circulating PAF during anaphylaxis (18) and the absence of mast cell–derived TNF-α. Pretreatment with anti–TNF-α resulted in abrogation of the late increase in hematocrit in both wild-type and W/Wvmice (Fig. 5 d). Therefore, it is likely that TNF-α is also a key cytokine in the development of a late anaphylactic reaction in W/Wv, even with a reduced capacity to produce this cytokine.

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