CCR6 is not necessary for functional effects of human CCL18 in a mouse model

CC chemokine ligand 18 (CCL18, also termed MIP-4, PARC, AMAC-1, DC-CK-1 and SCYA18) is a chemokine that has been implicated in several fibrotic pulmonary diseases associated with T-lymphocyte infiltration [1-5]. This cytokine has no known receptor and is present in humans but not in mice [6-9], although human CCL18 is fully functionally active in mice in vivo, causing chemotaxis of T-lymphocytes [3-5,9]. These observations suggest that although CCL18 was lost in mice after evolutionary separation from human ancestors, the receptor for it has been preserved in both mice and humans. Identification of a functional CCL18 receptor would allow for development of therapies targeting CCL18-driven lymphocytic inflammation and fibrosis. However, major efforts of numerous laboratories for more than a decade failed to identify a CCL18 receptor. At this point, excluding CCL18 receptor candidates becomes important for narrowing the spectrum of potential cell surface molecules that may band CCL18 and mediate its effects, and thus for avoiding duplicating the efforts of various investigators.It has been recently suggested [10] that CC chemokine receptor 6 (CCR6) may be a functional receptor for CCL18. CCR6 is known as the receptor for a different chemokine, CCL20 (also termed LARC or MIP-3α), and human CCL20 is biologically active in mice in vivo and on mouse cells in culture [11,12]. Therefore, we hypothesized that if CCR6 is a receptor for CCL18, the effects of human CCL18 in mice [3-5,9] may be mediated by mouse CCR6.To address this hypothesis, two types of experiments have been performed. In the first series of experiments, wild-type C57Bl/6 mice (The Jackson Laboratory, Bar Harbor, ME, USA) received intratracheal instillations of a replication-deficient recombinant adenoviral construct encoding human CCL18 (AdV-CCL18), exactly as described previously [3-5]. Control mice received similar amounts of AdV-NULL, which does not encode a cytokine. Three animals per group were analyze