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The Coding ECP 434(G>C) Gene Polymorphism Determines the Cytotoxicity of ECP but Has Minor Effects on Fibroblast-Mediated Gel Contraction and No Effect on RNase Activity¹

Jenny Rubin^2,*, Ulrika Zagai, Kristin Blom^*, Agneta Trulson^*, Åke Engström and Per Venge^*

^* Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden; Department of Medicine, Division of Respiratory Medicine, Karolinska Institutet, Stockholm, Sweden; and Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden

Eosinophil cationic protein (ECP) is a secretory protein of the eosinophil granulocyte, a cell involved in innate immunity. Functional studies have implicated ECP in numerous processes, such as tissue remodeling in allergic inflammation and cytotoxicity toward a variety of pathogens. Recent genetic studies have suggested that the ECP 434(G>C) polymorphism resulting in an arg97thr substitution would alter the function of ECP in vivo. Functional (in vitro) studies of ECP up until now have either been conducted with native preparations containing an unknown mixture of the ECP^97arg and ECP^97thr variants, or with recombinant proteins. Therefore, we have now for the first time extracted the native ECP^97arg and ECP^97thr variants from healthy blood donors and tested them functionally in vitro. Our results show that the arg97thr shift dramatically alters the cytotoxic capacity of ECP in vitro; the tested ECP^97arg variants were cytotoxic toward the small-cell lung cancer cell line NCI-H69, whereas ECP^97thr was noncytotoxic. RNase activity was unaffected by the arg97thr substitution. Both ECP^97arg and ECP^97thr stimulated fibroblast-mediated collagen gel contraction, an experimental model, which depicts wound healing, in a dose-dependent manner. In conclusion, our results demonstrate that the ECP 434(G>C) gene polymorphism affects the functional properties of native ECP, but also that there is a dissociation between different biological activities; the arg97thr substitution impairs the cytotoxic potential of ECP but less the gel contraction and not at all the RNase activity.

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 by grants from The Swedish Medical Research Council, the Swedish Heart and Lung Foundation, and the Swedish Asthma and Allergy Association.

² Address correspondence and reprint requests to Jenny Rubin, Department of Medical Sciences, Clinical Chemistry, Uppsala Academic Hospital, Uppsala, Sweden. E-mail address: jenny.eriksson{at}medsci.uu.se

³ Abbreviations used in this paper: ECP, eosinophil cationic protein; SNP, single nucleotide polymorphism; LMW-ECP, low m.w.-eosinophil cationic protein; SELDI-TOF MS, surface enhanced laser desorption/ionization-time of flight mass spectrometry.

This article has been cited by other articles:

				C. Woschnagg, J. Rubin, and P. Venge Eosinophil Cationic Protein (ECP) Is Processed during Secretion J. Immunol., September 15, 2009; 183(6): 3949 - 3954. [Abstract] [Full Text] [PDF]