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Molecular and Cellular Biology, August 2001, p. 5389-5395, Vol. 21, No. 16
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
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
-Glutamyl Leukotrienase Results in
Disruption of Leukotriene D4 Synthesis In Vivo and
Attenuation of the Acute Inflammatory Response
-glutamyl leukotrienase (GGL), a newly
identified member of the
-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.
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