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Generation of Anaphylatoxins by Human β-Tryptase from C3, C4, and C5¹

Yoshihiro Fukuoka^*, Han-Zhang Xia^*, Laura B. Sanchez-Muñoz, Anthony L. Dellinger^*, Luis Escribano and Lawrence B. Schwartz^2,*

^* Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298; and Centro de Estudios de Mastocitosis de Castilla La Mancha, Hospital Virgen del Valle, Toledo, Spain

Both mast cells and complement participate in innate and acquired immunity. The current study examines whether β-tryptase, the major protease of human mast cells, can directly generate bioactive complement anaphylatoxins. Important variables included pH, monomeric vs tetrameric forms of β-tryptase, and the β-tryptase-activating polyanion. The B12 mAb was used to stabilize β-tryptase in its monomeric form. C3a and C4a were best generated from C3 and C4, respectively, by monomeric β-tryptase in the presence of low molecular weight dextran sulfate or heparin at acidic pH. High molecular weight polyanions increased degradation of these anaphylatoxins. C5a was optimally generated from C5 at acidic pH by β-tryptase monomers in the presence of high molecular weight dextran sulfate and heparin polyanions, but also was produced by β-tryptase tetramers under these conditions. Mass spectrometry verified that the molecular mass of each anaphylatoxin was correct. Both β-tryptase-generated C5a and C3a (but not C4a) were potent activators of human skin mast cells. These complement anaphylatoxins also could be generated by β-tryptase in releasates of activated skin mast cells. Of further biologic interest, β-tryptase also generated C3a from C3 in human plasma at acidic pH. These results suggest β-tryptase might generate complement anaphylatoxins in vivo at sites of inflammation, such as the airway of active asthma patients where the pH is acidic and where elevated levels of β-tryptase and complement anaphylatoxins are detected.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grant RO1-AI27517 (to L.B.S.) from the National Institutes of Health and by the American Lung Association (to Y.F.).

² Address correspondence and reprint requests to Dr. Lawrence B. Schwartz, Virginia Commonwealth University, PO Box 980263, Richmond, VA 23298-0263. E-mail address: lbschwar{at}vcu.edu

³ Abbreviations used in this paper: HMW, high molecular weight; LMW, low molecular weight; DS5K, dextran sulfate of 5000 Da; DS500k, dextran sulfate of 500,000 Da.

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