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J. Biol. Chem., Vol. 281, Issue 51, 39088-39095, December 22, 2006

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Ligand Specificity of the Anaphylatoxin C5L2 Receptor and Its Regulation on Myeloid and Epithelial Cell Lines^*

Kay Johswich¹, Myriam Martin¹, Jessica Thalmann, Claudia Rheinheimer, Peter N. Monk, and Andreas Klos²

From the Department of Medical Microbiology, Medical School Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany and the Department of Neurology, School of Medicine and Biomedical Sciences, Sheffield S10 2RX, United Kingdom

During complement activation the pro-inflammatory anaphylatoxins C3a and C5a are generated, which interact with the C3a receptor and C5a receptor (CD88), respectively. C5a and its degradation product C5a-des-Arg⁷⁴ also bind to the C5a receptor-like 2 (C5L2). C3a and C3a-des-Arg⁷⁷, also called acylation-stimulating protein, augment triglyceride synthesis and glucose uptake in adipocytes and skin fibroblasts. Based on data obtained using transfected HEK293 and RBL cells, C5L2 is additionally proposed as a functional receptor for C3a and C3a-des-Arg⁷⁷. Here we use ¹²⁵I-ligand binding assays and flow cytometry with fluorescently labeled ligands to demonstrate that neither C3a nor C3a-des-Arg⁷⁷ binds to C5L2. C5L2 expression and its regulation are investigated on various cell lines by a novel C5L2-restricted binding assay and quantitative real time PCR. Dibutyryl cAMP and interferon- induce up-regulation of this receptor on myeloblastic cell lines (U937 and HL-60), whereas tumor necrosis factor- (TNF-) has no effect. In contrast, epithelial HeLa cells are found to constitutively express C5L2 but not the C5a receptor. In HeLa cells, interferon- and TNF- drastically reduce C5L2 expression. No C5a-dependent Ca²⁺ signaling is observed even in these cells endogenously expressing C5L2. Taken together, C5L2 is not a receptor for C3a or C3a-des-Arg⁷⁷. Thus, this receptor is unlikely to be directly involved in lipid metabolism. Instead, the identification of stimuli modifying C5L2 expression indicates that C5L2 is a highly regulated scavenger receptor for C5a and C5a-des-Arg⁷⁴.

Received for publication, October 16, 2006

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB566/A04 (to A. K.) and Wellcome Trust Project Grant 72231 (to P. N. M.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 49-511-532-4342; Fax: 49-511-532-4366; E-mail: Klos.Andreas{at}mh-hannover.de.

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