Proinflammatory role of glucocorticoid-induced TNF receptor-related gene in acute lung inflammation.
Glucocorticoid-induced TNFR-related gene (GITR) participates in the immune/inflammatory response. Because GITR expression has been described in cells other than T lymphocytes, we investigated whether it also modulates acute inflammatory response. Using GITR-deficient (GITR(-/-)) mice, we analyzed the role of GITR in the development of carrageenan-induced lung inflammation (pleurisy) by studying several proinflammatory markers 2-8 h after carrageenan injection. When compared with GITR(+/+), GITR(-/-) mice exhibited decreased production of turbid exudate containing a lower number of leukocytes. This was correlated with the reduction of inflammatory markers (including TNF-alpha, IL-1beta, myeloperoxidase, inducible NO synthase, and cyclooxygenase 2) in the pleural exudate and/or in the lung. Moreover, endothelial cells expressed lower levels of adhesion molecules. In lungs of GITR(+/+) mice, GITR ligand expression was not modulated during pleurisy, while that of GITR increased, as a consequence of increased infiltration by GITR-expressing cells and of GITR up-regulation in macrophages and endothelial cells. Finally, cotreatment of GITR(+/+) mice with carrageenan and Fc-GITR fusion protein decreased the number of inflammatory cells (pleural macrophages and lung neutrophils) as compared with carrageenan treatment alone, confirming that GITR plays a role in the modulation of pleurisy.
Cuzzocrea
Salvatore
S
Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. salvator@unime.it
Nocentini
Giuseppe
G
Di Paola
Rosanna
R
Agostini
Massimiliano
M
Mazzon
Emanuela
E
Ronchetti
Simona
S
Crisafulli
Concetta
C
Esposito
Emanuela
E
Caputi
Achille P
AP
Riccardi
Carlo
C
D000208:Acute Disease; D000818:Animals; D002351:Carrageenan / Q000008:administration & dosage; D002463:Cell Membrane Permeability / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D007958:Leukocyte Count; D007962:Leukocytes / Q000473:pathology; D008024:Ligands; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D010996:Pleural Effusion / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D010998:Pleurisy / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D048069:Tumor Necrosis Factors / Q000096:biosynthesis
D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids; D018836:Inflammation Mediators; D008024:Ligands; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; D002351:Carrageenan