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Science 1 October 1999:
Vol. 286. no. 5437, pp. 113 - 117
DOI: 10.1126/science.286.5437.113
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Reports

Regulation of Intestinal alpha -Defensin Activation by the Metalloproteinase Matrilysin in Innate Host Defense

Carole L. Wilson, 1* Andre J. Ouellette, 23 Donald P. Satchell, 2 Tokiyoshi Ayabe, 2 Yolanda S. López-Boado, 1 Jennifer L. Stratman, 1 Scott J. Hultgren, 4 Lynn M. Matrisian, 5 William C. Parks 1

Precursors of alpha -defensin peptides require activation for bactericidal activity. In mouse small intestine, matrilysin colocalized with alpha -defensins (cryptdins) in Paneth cell granules, and in vitro it cleaved the pro segment from cryptdin precursors. Matrilysin-deficient (MAT-/-) mice lacked mature cryptdins and accumulated precursor molecules. Intestinal peptide preparations from MAT-/- mice had decreased antimicrobial activity. Orally administered bacteria survived in greater numbers and were more virulent in MAT-/- mice than in MAT+/+ mice. Thus, matrilysin functions in intestinal mucosal defense by regulating the activity of defensins, which may be a common role for this metalloproteinase in its numerous epithelial sites of expression.

1 Department of Pediatrics, Division of Allergy and Pulmonary Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
2 Department of Pathology and
3 Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, CA 92697, USA.
4 Department of Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, MO 63110, USA.
5 Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
*   To whom correspondence should be addressed. E-mail: wilson_c{at}kids.wustl.edu

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A. Vidrich, J. M. Buzan, S. Barnes, B. K. Reuter, K. Skaar, C. Ilo, F. Cominelli, T. Pizarro, and S. M. Cohn (2005)
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From The Cover: Expression of an additional cathelicidin antimicrobial peptide protects against bacterial skin infection.
P. H. A. Lee, T. Ohtake, M. Zaiou, M. Murakami, J. A. Rudisill, K. H. Lin, and R. L. Gallo (2005)
PNAS 102, 3750-3755
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Nod2-Dependent Regulation of Innate and Adaptive Immunity in the Intestinal Tract.
K. S. Kobayashi, M. Chamaillard, Y. Ogura, O. Henegariu, N. Inohara, G. Nunez, and R. A. Flavell (2005)
Science 307, 731-734
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Tissue Inhibitor of Metalloproteinase 1 Regulates Resistance to Infection.
M. M. Lee, B.-J. Yoon, K. Osiewicz, M. Preston, B. Bundy, A. M. van Heeckeren, Z. Werb, and P. D. Soloway (2005)
Infect. Immun. 73, 661-665
   Abstract »    Full Text »    PDF »
Rapid evolution and diversification of mammalian {alpha}-defensins as revealed by comparative analysis of rodent and primate genes.
A. Patil, A. L. Hughes, and G. Zhang (2004)
Physiol Genomics 20, 1-11
   Abstract »    Full Text »    PDF »
Structure-Activity Relationships in Defensin Dimers: A NOVEL LINK BETWEEN {beta}-DEFENSIN TERTIARY STRUCTURE AND ANTIMICROBIAL ACTIVITY.
D. J. Campopiano, D. J. Clarke, N. C. Polfer, P. E. Barran, R. J. Langley, J. R. W. Govan, A. Maxwell, and J. R. Dorin (2004)
J. Biol. Chem. 279, 48671-48679
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NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal {alpha}-defensin expression.
J Wehkamp, J Harder, M Weichenthal, M Schwab, E Schaffeler, M Schlee, K R Herrlinger, A Stallmach, F Noack, P Fritz, et al. (2004)
Gut 53, 1658-1664
   Abstract »    Full Text »    PDF »
Pseudomonas aeruginosa Flagellin and Alginate Elicit Very Distinct Gene Expression Patterns in Airway Epithelial Cells: Implications for Cystic Fibrosis Disease.
L. M. Cobb, J. C. Mychaleckyj, D. J. Wozniak, and Y. S. Lopez-Boado (2004)
J. Immunol. 173, 5659-5670
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Impaired Immunity to Intestinal Bacterial Infection in Stromelysin-1 (Matrix Metalloproteinase-3)-Deficient Mice.
C. K. F. Li, S. L. F. Pender, K. M. Pickard, V. Chance, J. A. Holloway, A. Huett, N. S. Goncalves, J. S. Mudgett, G. Dougan, G. Frankel, et al. (2004)
J. Immunol. 173, 5171-5179
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Functional Analysis of the {alpha}-Defensin Disulfide Array in Mouse Cryptdin-4.
A. Maemoto, X. Qu, K. J. Rosengren, H. Tanabe, A. Henschen-Edman, D. J. Craik, and A. J. Ouellette (2004)
J. Biol. Chem. 279, 44188-44196
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NF-{kappa}B- and AP-1-Mediated Induction of Human Beta Defensin-2 in Intestinal Epithelial Cells by Escherichia coli Nissle 1917: a Novel Effect of a Probiotic Bacterium.
J. Wehkamp, J. Harder, K. Wehkamp, B. W.-v. Meissner, M. Schlee, C. Enders, U. Sonnenborn, S. Nuding, S. Bengmark, K. Fellermann, et al. (2004)
Infect. Immun. 72, 5750-5758
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Temporin A and Related Frog Antimicrobial Peptides Use Formyl Peptide Receptor-Like 1 as a Receptor to Chemoattract Phagocytes.
Q. Chen, D. Wade, K. Kurosaka, Z. Y. Wang, J. J. Oppenheim, and D. Yang (2004)
J. Immunol. 173, 2652-2659
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Degranulation of Paneth Cells via Toll-Like Receptor 9.
C. Rumio, D. Besusso, M. Palazzo, S. Selleri, L. Sfondrini, F. Dubini, S. Menard, and A. Balsari (2004)
Am. J. Pathol. 165, 373-381
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Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
K. Fujiwara, M. Ochiai, T. Ohta, M. Ohki, H. Aburatani, M. Nagao, T. Sugimura, and H. Nakagama (2004)
Carcinogenesis 25, 1495-1505
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The Androgen-Regulated Epididymal Sperm-Binding Protein, Human {beta}-Defensin 118 (DEFB118) (Formerly ESC42), Is an Antimicrobial {beta}-Defensin.
S. Yenugu, K. G. Hamil, Y. Radhakrishnan, F. S. French, and S. H. Hall (2004)
Endocrinology 145, 3165-3173
   Abstract »    Full Text »    PDF »


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