Cytokine and Estrogen Stimulation of Endothelial Cells Augment Activation of the Prekallikrein-High Molecular Weight Kininogen Complex: Implications for Hereditary Angioedema (HAE)

Publication date: Available online 5 November 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Kusumam Joseph, Baby G. Tholanikunnel, Allen P. Kaplan
BackgroundWhen the prekallikrein-high molecular weight kininogen complex is bound to endothelial cells, prekallikrein is stoichiometrically converted to kallikrein due to release of heat shock protein-90 (Hsp90). While bradykinin formation is typically initiated by factor XII autoactivation it is also possible to activate factor XII either by kallikrein, thus formed, or plasmin.RationaleSince attacks of hereditary angioedema can be related to infection and/or exposure to estrogen, we questioned whether estrogen or cytokine stimulation of endothelial cells could augment release of Hsp90 and prekallikrein activation. We also tested release of profibrinolytic enzymes, urokinase and tissue plasminogen activator (TPA) as a source for plasmin formation.MethodsCells were stimulated with agonists and secretion of Hsp90, urokinase, and TPA, were measured in the culture supernatants by ELISA. Activation of the prekallikrein-HK complex was measured employing pro-phe-arg-p-nitroanilide reflecting kallikrein formation.ResultsHsp90 release was stimulated with optimal doses of estradiol, IL-1, and TNFα (10ng/ml) from 15 min to 120 min. TPA release was not augmented by any of the agonists tested but urokinase was released by IL-1, TNFα and thrombin (positive control), but not estrogen. Augmented activation of the prekallikrein-HK complex to generate kallikrein was seen with each agonist that releases Hsp90. Addition of 0.1% factor XII relative to prekallikrein-HK leads to rapid formation of kallikrein; factor XII alone does not autoactivate.ConclusionsInterleukin-1, TNFα, and estrogen stimulate release of Hsp90 and augment activation of the prekallikrein-HK complex to generate kallikrein and bradykinin. IL-1 and TNFα stimulate release of urokinase, which can convert plasminogen to plasmin and represents a possible source for plasmin generation in all types of HAE, but particularly HAE with normal C1 inhibitor (HAE-N) with a factor XII mutation. Both kallikrein and plasmin activate factor XII; kallikrein is 20 times more potent on a molar basis.Clinical ImplicationAttacks of angioedema in patients with HAE may be initiated by estrogen (endogenous or exogenous) or by infection. Cytokine or estrogen stimulation of endothelial cells and augmented activation of the prekallikrein-HK complex could potentially initiate this process.

Teaser

Activation of endothelial cells by cytokines and estrogen augment secretion of Hsp90, which forms a zinc-dependent trimolecular complex with HK-prekallikrein and converts prekallikrein to kallikrein. Cytokines also stimulate release of urokinase. Novel mechanisms for initiation of bradykinin formation in hereditary angioedema by infection or estrogen are suggested.


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