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Expression and Functional Activity of the IL-8 Receptor Type CXCR1 and CXCR2 on Human Mast Cells¹

Undine Lippert^*, Metin Artuc^2,*, Andreas Grützkau^*, Annelie Möller^*, Anna Kenderessy-Szabo, Dirk Schadendorf^*, Johannes Norgauer, Karin Hartmann^*, Reinhard Schweitzer-Stenner^§, Thorsten Zuberbier^*, Beate M. Henz^* and Sabine Krüger-Krasagakes^*

^* Department of Dermatology, Charité, Campus Virchow Klinikum, Humboldt Universität of Berlin, Berlin, Germany; Albert Szent-Györgyi Medical University, Szeged, Hungary; Albrecht-Ludwigs-Universität, Freiburg, Germany; and ^§ Institute for Experimental Physics, Universität Bremen, Bremen, Germany

To further elucidate mechanisms involved in mast cell accumulation at sites of cutaneous inflammation, we have studied the ability of human leukemic mast cells (HMC-1 cells) to express functionally active IL-8 receptors. Expression of mRNA for both types of IL-8 receptors (CXCR1 and CXCR2) was demonstrated by PCR and of both proteins by flow cytometry. Binding and competition studies with ¹²⁵I-labeled IL-8 and its homologue melanoma growth stimulating activity (¹²⁵I-labeled MGSA) revealed two specific binding sites for IL-8, K₁ = 1.1 x 10¹¹ M^-1 and K₂ = 5 x 10⁷ M^-1; and for MGSA, K₁ = 2.8 x 10¹⁰ M^-1 and K₂ = 5 x 10⁷ M^-1. This finding was supported by a dose-dependent rise of cytosolic free calcium concentration ([Ca²⁺]_i) induced by both chemokines and to a lesser extent by the homologue neutrophil-activating peptide-2 (NAP-2). A significant migratory response of human leukemic mast cells (HMC-1) was observed with all three chemokines at a range from 10^-8 M to 10^-9 M. Moreover, the formation of cellular F-actin was induced in a rapid, dose-dependent fashion, with a maximally 1.7-fold increase at 10^-7 M. Using postembedding immunoelectron microscopy, we could show the expression of CXCR1 on the cytoplasmatic membrane of isolated human skin mast cells whereas CXCR2 was located in mast cell-specific granules. These findings demonstrate for the first time the functional expression of both types of IL-8 receptors on human mast cells, suggesting a role for their ligands during mast cell activation and recruitment.