Treatment of allergic airway inflammation and hyperresponsiveness by imiquimod modulating transcription factors T-bet and GATA-3.
BACKGROUND
Imiquimod is an imidazoquinoline, which class of compounds are known to have antiviral and antitumoural properties. In recent studies, it was shown that imiquimod modulates the T helper cell type Th1/Th2 response by inducing the production of Th1 cytokines like IFN-gamma, and by inhibiting the Th2 cytokines like interleukin (IL)-4. Several investigators have shown that T-bet and GATA-3 are master Th1 and Th2 regulatory transcription factors. This study investigated whether imiquimod treatment inhibited airway inflammation by modulating transcription factors T-bet and GATA-3.


METHODS
Thirty-six male SD rats were randomly divided into a control group, an asthmatic group, and an imiquimod group, which was exposed to an aerosol of 0.15% imiquimod. Twenty-four hours after the last ovalbumin (OVA) challenge, airway responsiveness was measured and changes in airway histology were observed. The concentrations of IL-4, IL-5 and IFN-gamma in bronchoalveolar lavage fluid (BALF) and serum were measured by enzyme linked immunosorbent assay (ELISA). The mRNA expressions of IL-4, IL-5, IFN-gamma, T-bet and GATA-3 in lung and in CD4(+) T cells were determined by reverse transcription polymerase chain reaction (RT-PCR). The protein expressions of T-bet and GATA-3 were measured by Western blot.


RESULTS
It was demonstrated that imiquimod 1) attenuated OVA induced airway inflammation; 2) diminished the degree of airway hyperresponsiveness (AHR); 3) decreased the Th2 type cytokines and increased Th1 type cytokines mRNA and protein levels; 4) modulated the Th1/Th2 reaction by inhibiting GATA-3 production and increasing T-bet production.


CONCLUSIONS
Imiquimod treatment inhibits OVA induced airway inflammation by modulating key master switches GATA-3 and T-bet that result in committing T helper cells to a Th1 phenotype.
Bian
Tao
T
Department of Respiratory Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Yin
Kai-sheng
KS
Jin
Shu-xian
SX
Zhang
Xi-long
XL
Zhou
Jin-yong
JY
Ma
Xiu-qin
XQ
Hu
Jing-jing
JJ
De
Wei
W
D000280:Administration, Inhalation; D000634:Aminoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D001980:Bronchi / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004804:Eosinophils / Q000502:physiology; D050990:GATA3 Transcription Factor / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D000077271:Imiquimod; D008168:Lung / Q000473:pathology; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000235:genetics*; D000098815:T-bet Transcription Factor
D000634:Aminoquinolines; D016207:Cytokines; D050990:GATA3 Transcription Factor; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D010047:Ovalbumin; D000077271:Imiquimod