Genetic ablation of PARP-1 protects against oxazolone-induced contact hypersensitivity by modulating oxidative stress.
Contact hypersensitivity (CHS) reaction is a form of delayed-type of hypersensitivity caused by contact allergens such as oxazolone (OXA). In previous studies it has been shown that poly(ADP-ribose) polymerase (PARP) inhibition reduces the extent of inflammation in CHS. We aimed to shed light on the molecular events causing the protective effect of PARP inhibitors. PARP-1 and -2 knockout mice were sensitized by abdominal delivery of OXA, and a week later CHS was induced by applying OXA on the ears of the mice. PARP-1(-/-) mice were protected against OXA-induced CHS in contrast to PARP-2(-/-) mice. In PARP-1(-/-) mice, neutrophil infiltration was reduced in line with the suppressed expression of proinflammatory cytokines, cell adhesion factors, and matrix metalloproteinase-9, which is likely because of impaired activation of NF-κB p65 and activating transcription factor-2, the two redox-sensitive transcription factors. Moreover, reduced nitrosative and oxidative stress was observed under inflammatory conditions in the PARP-1(-/-) mice when compared with PARP-1(+/+). In conclusion, PARP-1 activation is necessary for proinflammatory gene expression through which PARP-1 enhances neutrophil infiltration and hence oxidative/nitrosative stress, forming a vicious circle, and further aggravating the inflammatory process. Our data identify PARP-1 as a possible target in CHS.
Brunyánszki
Attila
A
Department of Medical Chemistry, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary.
Hegedus
Csaba
C
Szántó
Magdolna
M
Erdélyi
Katalin
K
Kovács
Katalin
K
Schreiber
Valérie
V
Gergely
Szabolcs
S
Kiss
Borbála
B
Szabó
Eva
E
Virág
László
L
Bai
Péter
P
D000276:Adjuvants, Immunologic / Q000633:toxicity; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D003877:Dermatitis, Contact / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D007509:Irritants / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000502:physiology; D010081:Oxazolone / Q000633:toxicity*; D018384:Oxidative Stress / Q000235:genetics*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D000276:Adjuvants, Immunologic; D007509:Irritants; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D010081:Oxazolone; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse