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Molecular and Cellular Biology, August 2001, p. 5389-5395, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5389-5395.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Disruption of gamma -Glutamyl Leukotrienase Results in Disruption of Leukotriene D4 Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Zheng-Zheng Shi,1 Bing Han,1 Geetha M. Habib,1 Martin M. Matzuk,1,2,3 and Michael W. Lieberman1,2,*

Departments of Pathology,1 Molecular and Cellular Biology,2 and Molecular and Human Genetics,3 Baylor College of Medicine, Houston, Texas 77030

Received 3 April 2001/Accepted 23 May 2001

To study the function of gamma -glutamyl leukotrienase (GGL), a newly identified member of the gamma -glutamyl transpeptidase (GGT) family, we generated null mutations in GGL (GGLtm1) and in both GGL and GGT (GGLtm1-GGTtm1) by a serial targeting strategy using embryonic stem cells. Mice homozygous for GGLtm1 show no obvious phenotypic changes. Mice deficient in both GGT and GGL have a phenotype similar to the GGT-deficient mice, but ~70% of these mice die before 4 weeks of age, at least 2 months earlier than mice deficient only in GGT. These double-mutant mice are unable to cleave leukotriene C4 (LTC4) to LTD4, indicating that this conversion is completely dependent on the two enzymes, and in some organs (spleen and uterus) deletion of GGL alone abolished more than 90% of this activity. In an experimental model of peritonitis, GGL alone is responsible for the generation of peritoneal LTD4. Further, during the development of peritonitis, GGL-deficient mice show an attenuation in neutrophil recruitment but not of plasma protein influx. These findings demonstrate an important role for GGL in the inflammatory response and suggest that LTC4 and LTD4 have distinctly different functions in the inflammatory process.

* Corresponding author. Mailing address: Department of Pathology, One Baylor Plaza, Baylor College of Medicine, Houston, TX 77030. Phone: (713) 798-6501. Fax: (713) 798-6001. E-mail: mikel{at}bcm.tmc.edu.

Molecular and Cellular Biology, August 2001, p. 5389-5395, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5389-5395.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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