Effect of tumour necrosis factor-alpha receptor 1 genetic deletion on carrageenan-induced acute inflammation: a comparison with etanercept.
In the present study, we used tumour necrosis factor-alpha receptor 1 knock-out mice (TNF-alphaR1KO) to evaluate an in vivo role of TNF-alphaR1 on the pathogenesis of inflammatory diseases. We used a murine model of carrageenan-induced acute inflammation (pleurisy), a preclinical model of airway inflammation. The data proved that TNF-alphaR1KO were resistant to carrageenan-induced acute inflammation compared with TNF-alpha wild-type mice. TNF-alphaR1KO showed a significant reduction in accumulation of pleural exudate and in the number of inflammatory cells, in lung infiltration of polymorphonuclear leucocytes and lipid peroxidation and showed a decreased production of nitrite/nitrate in pleural exudates. Furthermore, the intensity and degree of the adhesion molecule intercellular adhesion molecule-1 and P-selectin, Fas ligand (FasL), inducible nitric oxide sythase and nitrotyrosine determined by immunohistochemical analysis were reduced markedly in lung tissues from TNF-alphaR1KO at 4 h and 24 h after carrageenan injection. Moreover, TNF-alpha and interleukin-1beta concentrations were reduced in inflamed areas and in pleural exudates from TNF-alphaR1KO. To support the results generated using pleural inflammation, carrageenan-induced paw oedema models were also performed. In order to elucidate whether the observed anti-inflammatory effects were related to the inhibition of TNF-alpha, we also investigated the effect of etanercept, a TNF-alpha soluble receptor construct, on carrageenan-induced pleurisy. The treatment with etanercept (5 mg/kg subcutaneously 2 h before the carrageenan injection) reduces markedly both laboratory and histological signs of carrageenan-induced pleurisy. Our results showed that administration of etanercept resulted in the same outcome as that of deletion of the TNF-alphaR1 receptor, adding a new insight to TNF-alpha as an excellent target by therapeutic applications.
Mazzon
E
E
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.
Esposito
E
E
Di Paola
R
R
Muià
C
C
Crisafulli
C
C
Genovese
T
T
Caminiti
R
R
Meli
R
R
Bramanti
P
P
Cuzzocrea
S
S
D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002351:Carrageenan; D004487:Edema / Q000188:drug therapy / Q000276:immunology; D000068800:Etanercept; D053222:Fas Ligand Protein / Q000032:analysis; D017353:Gene Deletion; D006614:Hindlimb; D007074:Immunoglobulin G / Q000627:therapeutic use; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007375:Interleukin-1 / Q000032:analysis; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D019007:P-Selectin / Q000032:analysis; D010998:Pleurisy / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D015415:Biomarkers; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D007375:Interleukin-1; D019007:P-Selectin; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C002744:3-nitrotyrosine; D014443:Tyrosine; D002351:Carrageenan; D000068800:Etanercept