International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

TUESDAY OCTOBER 19

10.00am – 10.15am

IDENTIFICATION OF THE IL-17 RECEPTOR-RELATED MOLECULE, IL-17RC AS A RECEPTOR FOR IL-17A AND IL-17F

Kuestner R, Brandt C, Gao Z, Ostrander C, Bort S, Taft D, Bilsborough J, Lewis K, Jaspers S, Dillon S, Lewis P, Topouzis S, Rixon M, Chan C, Moore M, Reardon B, Bukowski T, Moore B, West J, Parrish-Novak J, Levin SD

ZymoGenetics, Inc., Seattle, United States

The pro-inflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity, share many biological properties, and are both produced by activated T cells.  They have both been implicated as factors that contribute to the progression of various autoimmune and inflammatory diseases including rheumatoid arthritis and asthma.  In fact, reagents that negate IL-17A function significantly ameliorate disease incidence and severity in several mouse models of human disease.  IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17R), but the receptor for IL-17F has not yet been identified.  We now report that we have identified the IL-17R-related molecule, IL-17RC as the receptor for IL-17F.  However, we have also noted that this receptor binds to both IL-17A and IL-17F with a similar high affinity.  IL-17R on the other hand, binds IL-17A with high affinity, but binds IL-17F with very low affinity.  Consistent with this, we have shown that a soluble form of IL-17R blocks IL-17A binding and signaling in cells expressing either receptor, but does not interfere with binding or function of IL-17F to IL-17RC.  In contrast, a soluble form of IL-17RC inhibits the interaction and effects of both IL-17A and IL-17F in cells expressing either receptor.  Since IL-17A intervention has been proposed as an effective therapy for several auto-immune diseases, we propose that using soluble IL-17RC to inhibit effects of both IL-17A and IL-17F will have advantages over therapies that target only one of these two cytokines.

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