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

Abstract

To study the function of γ-glutamyl leukotrienase (GGL), a newly identified member of the γ-glutamyl transpeptidase (GGT) family, we generated null mutations in GGL (GGL^tm1) and in both GGL and GGT (GGL^tm1-GGT^tm1) by a serial targeting strategy using embryonic stem cells. Mice homozygous for GGL^tm1 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.

ACKNOWLEDGMENTS

This work was supported by NIH grant ES-07827.

We thank Donna Atwood, Andrew Bahler, Christopher Danney, Cathy Guo, and Pei Wang for technical assistance.