Abstract
The migration of polymorphonuclear leukocytes from the blood to sites of infection in tissues is a hallmark of the innate immune response. Formylated peptides produced as a byproduct of bacterial protein synthesis are powerful chemoattractants for leukocytes. Formyl peptides bind to two different G protein-coupled receptors (formyl peptide receptor (FPR) and the low affinity formyl peptide receptor-like-1 (FPRL1)) to initiate a signal transduction cascade leading to cell activation and migration. Our analysis of expressed sequences from many cDNA libraries draws attention to the fact that FPRs are widely expressed in nonlymphoid tissues. Here we demonstrate that FPRs are expressed by normal human lung and skin fibroblasts and the human fibrosarcoma cell line HT-1080. The expression on fibroblasts of receptors for bacteria-derived peptides raises questions about the possible function of these receptors in nonleukocyte cells. We studied the function of FPRs on fibroblasts and find that stimulation with fMLP triggers dose-dependent migration of these cells. Furthermore, fMLP induces signal transduction including intracellular calcium flux and a transient increase in F-actin. The fMLP-induced adhesion and motility of fibroblasts on fibronectin require functional protein kinase C and phosphatidylinositol 3-kinase. This first report of a functional formyl peptide receptor in cells of fibroblast origin opens new possibilities for the role of fibroblasts in innate immune responses.
Highlights
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Because signaling through formyl peptide receptor (FPR) results in activation of integrins responsible for neutrophil adhesion and migration (30 –34), we investigated the effect of fMLP treatment on fibroblast cell adhesion to specific extracellular matrices (ECM)
We have shown that human fibroblasts express functional FPRs
Summary
FPR, formyl peptide receptor; PKC, protein kinase C; FPRL1, FPR-like 1; FPRL2, FPR-like 2; WKYMVm, Trp-Lys-Tyr-Met-Val-DMet-NH2; BocFLFLF, BOC-Phe-Leu-Phe-Leu-Phe; FNLPNTL-FL, formyl-norleucyl-Leu-Phe-norleucyl-Tyr-Lys-fluorescein; EST, expressed sequence tag; ECM, extracellular matrix; AM, acetoxymethyl ester. A search of the Human Expressed Sequence Tagged (EST) database reveals expression of FPR and FPRL1 in multiple tissues (Table I). We were surprised at the abundance of ESTs for FPR and FPRL1 in these nonlymphoid tissues This nonleukocyte expression was observed by Becker et al [10] who show staining of multiple tissues and cell types with rabbit polyclonal antisera against the C terminus of FPR. A variety of experimental approaches indicate that these receptors are able to induce intracellular signaling events leading to fibroblast motility. This first report of a functional FPR in cells of fibroblast origin suggests that these cells are able to respond directly to bacterial presence potentially contributing to innate immune responses
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