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Silencing the Formylpeptide Receptor FPR by Short-Interfering RNA

Laboratories of Molecular Immunoregulation (P.I., Y.Z., J.H., J.M.W.) and Experimental Immunology (X.Z.), Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; Basic Research Program (W.G.), SAIC-Frederick, National Cancer Institute at Frederick, Frederick, Maryland; Institute for Nutritional Sciences (Y.L.), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China; and Cancer Research Institute (J.H.), Xiang-Ya Medical School, Central-Southern University, Changsha, People's Republic of China

A double-stranded short-interfering RNA (siRNA) was designed to attenuate the expression and function of the formylpeptide receptor FPR, a G protein-coupled receptor mediating migration and activation of phagocytic leukocytes in response to bacterial chemotactic formylpeptides. Retrovirus-based constructs were generated to introduce FPR-siRNA into a rat leukemia cell line transfected to overexpress FPR. Cells infected with FPR-siRNAT28, which targets the nucleotides 926 to 944 of FPR mRNA corresponding to the third extracellular loop of the putative receptor protein, showed significantly reduced expression of FPR mRNA and protein, in association with impaired calcium mobilization and chemotactic responses to peptide agonists. Direct transduction of synthetic FPR-siRNAT28 into human macrophages also inhibited the expression of FPR and abrogated cell chemotaxis and the release of superoxide anions induced by the bacterial formylpeptide. FPR-siRNA additionally abrogated the expression and function of FPR in a human malignant glioma cell line. Our study demonstrates successful application of siRNA to silence a G protein-coupled chemoattractant receptor involved in inflammation and suggests the potential to use this approach in studies of receptor regulation and prevention of undesirable side effects associated with FPR activation.

Address correspondence to: Dr. Ji Ming Wang, Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560, Room 31-40, Frederick, MD 21702-1201. E-mail: wangji{at}mail.ncifcrf.gov

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