4.5 Article

Recombinant protein glutathione S-transferases P1 attenuates inflammation in mice

Journal

MOLECULAR IMMUNOLOGY
Volume 46, Issue 5, Pages 848-857

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2008.09.010

Keywords

Rodent; Monocytes/macrophages; Endotoxin shock; Inflammation; Cytokines

Funding

  1. Major State Basic Research Development Program of China [2002CB513004]
  2. National Nature Science Foundation of China [30672473, 30670825]

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We have reported that intracellular glutathione S-transferases P1 (GSTP1) suppresses LPS (lipopolysaccharide)-induced excessive production of pro-inflammatory factors by inhibiting LPS-stimulated MAPKs (mitogen-activated protein kinases) as well as NF-kappa B activation. But under pathogenic circumstances, physiologic levels of GSTP1 are insufficient to stem pro-inflammatory signaling. Here we show that LPS-induced up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW246.7 cells is significantly reduced by incubating cells with recombinant GSTP1 protein. In vivo study demonstrates that treatment of mice (i.p.) with recombinant GSTP1 protein effectively suppresses the devastating effects of acute inflammation, which includes reduction of mortality rate of endotoxic shock, alleviation of LPS-induced acute lung injury and abrogation of thioglycolate (TG)-induced peritoneal deposition of leukocytes and polymorphonuclear cells (PMNs). Meanwhile, GSTP1 prevented LPS-induced TNF-alpha, IL-1 beta, MCP-1 and NO production. Further investigation by using confocal microscopy and flow cytometry shows that recombinant GSTP1 protein can be delivered into RAW246.7 cells, mouse peritoneal macrophages and HEK 293 cells suggesting that extracellular GSTP1 protein could be transported across plasma membrane and act as a cytosolic protein. In conclusion our research demonstrates a new finding that increasing cellular GSTP1 level by supplement of recombinant GSTP1 effectively suppresses the devastating effects of acute inflammation. (C) 2008 Elsevier Ltd. All rights reserved.

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