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Eosinophil Ribonucleases and Their Cutaneous Lesion-Forming Activity¹

Douglas A. Plager^*,2, Mark D. P. Davis^*, Amy G. Andrews, Michael J. Coenen^*, Terry J. George^*, Gerald J. Gleich^, and Kristin M. Leiferman^3,*

^* Department of Dermatology, Department of Comparative Medicine, Department of Immunology, and Department of Medicine, Mayo Clinic, Rochester, MN 55905

Eosinophil granule proteins are deposited in cutaneous lesions in many human diseases, but how these proteins contribute to pathophysiology is obscure. We injected eosinophil cationic protein (ECP or RNase 3), eosinophil-derived neurotoxin (EDN or RNase 2), eosinophil peroxidase (EPO), and major basic protein-1 (MBP1) intradermally into guinea pig and rabbit skin. ECP and EDN each induced distinct skin lesions at 2.5 µM that began at 2 days, peaking at 7 days and persisting up to 6 wk. These lesions were ulcerated (ECP) or crusted (EDN) with marked cellular infiltration. EPO and MBP1 (10 µM) each produced perceptible induration and erythema with moderate cellular infiltration resolving within 2 wk. ECP and EDN localized to dermal cells within 2 days, whereas EPO and MBP1 remained extracellular. Overall, cellular localization and RNase activity of ECP and EDN were critical for lesion formation; differential glycosylation, net cationic charge, or RNase activity alone did not account for lesion formation. Ulcerated lesions from patients with the hypereosinophilic syndrome showed ECP and EDN deposition comparable to that in guinea pig skin. In conclusion, ECP and EDN disrupt skin integrity and cause inflammation. Their presence in ulcerative skin lesions may explain certain findings in human eosinophil-associated diseases.

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 National Institutes of Health Grants AI 11483, AI 09728, AI 07047 (Training Grant), AI 34577, and AI 50494; the American Academy of Allergy, Asthma and Immunology Women Physicians in Allergy Grant (to K.M.L.); and by The Mayo Foundation, the Kieckhefer Foundation, and the Dr. Smith H. and Lucille Gibson Postdoctoral Research Fellowship in Dermatology (to D.A.P.).

² Address correspondence and reprint requests to Dr. Douglas A. Plager, Department of Dermatology, Mayo Clinic, Guggenheim 4-94, 200 First Street SW, Rochester, MN 55905. E-mail address: plager.douglas{at}mayo.edu

³ Current address: Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, UT 84132.

⁴ Abbreviations used in this paper: ECP, eosinophil cationic protein; Ang, pyroglu-angiogenin; CM, carboxymethyl; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase; HES, hypereosinophilic syndrome; MBP1, major basic protein-1.