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β-Defensins are cationic peptides produced by epithelial cells that have been proposed to be an important component of immune function at mucosal surfaces. Similarities between mammalian β-defensins may permit the use of murine models to further define the role of these peptides in innate host defense. Murine β-defensin-3 (mBD-3) is a peptide that exhibits homology at the gene level to human β-defensin-2 (hBD-2), one of four β-defensins identified in man. The purpose of this study was to determine the antimicrobial activity of mBD-3, the tissue distribution of mBD-3 expression, and the effect of gram-negative bacterial infection on mBD-3 expression. Based on the sequence deduced from mBD-3 cDNA, a 40-amino acid peptide was assembled using automated [n-(9-fluorenyl)methoxycarbonyl] solid-phase synthesis. The antimicrobial activity of synthetic mBD-3 was evaluated in microdilution broth assays using bacterial and fungal organisms. mBD-3 mRNA expression was assayed by polymerase chain reaction (PCR) using cDNA derived from a panel of tissues. Expression of mBD-3 was also evaluated in tissues obtained from mice 24 h after intraperitoneal infection with Escherichia coli using reverse transcriptase (RT)-PCR. Synthetic mBD-3 inhibited the growth of E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans at concentrations from 25 to 50 μg/mL. Constitutive expression of mBD-3 mRNA was not consistently found in any organ using RT-PCR. In an E. coli peritonitis model, expression of mBD-3 mRNA was upregulated only in the esophagus and tongue. We conclude that mBD-3 is an inducible peptide with limited tissue expression during E. coli peritonitis. Because it exhibits broad-spectrum antimicrobial activity, this peptide may serve as an innate defense against microbial invasion at specific mucosal surfaces in the mouse.