Trp-Arg-Trp-Trp-Trp-Trp antagonizes formyl peptide receptor like 2-mediated signaling

Although formyl peptide receptor like 2 (FPRL2) has been regarded as an important classical chemoattractant receptor, its functional role and signaling pathway have not been fully investigated, because of the lack of its specific ligand. Recently F2L, a heme-binding protein fragment peptide, has been reported as an FPRL2-selective endogenous agonist. In the present study, we examined the effect of Trp-Arg-Trp-Trp-Trp-Trp-CONH₂ (WRWWWW, WRW⁴), on F2L-induced cell signaling. WRW⁴ inhibited the activation of FPRL2 by F2L, resulting in the complete inhibition of intracellular calcium increase and chemotactic migration induced by F2L. WRW⁴ also completely inhibited F2L-induced NF-κB activation in FPRL2-transfected HEK293 cells. WRW⁴ specifically inhibited F2L-induced intracellular calcium increase and chemotactic migration in mature monocyte-derived dendritic cells, which express FPRL2 but not the other FPR family. Taken together, WRW ⁴ is the first FPRL2 antagonist and is expected to be useful in the study of FPRL2 signaling and in development of drugs against FPRL2-related cellular responses.