A critical role for Pin1 in allergic pulmonary eosinophilia in rats.
BACKGROUND
Infiltration, accumulation, and degranulation of eosinophils in the lung are hallmarks of active allergic asthma. The pulmonary response to inhaled allergen triggers the secretion of eosinophil chemoattractants and antiapoptotic cytokines, including GM-CSF, IL-3, IL-4, IL-5, and eotaxin, among others. We recently showed that in vitro Pin1 regulated eosinophil production of and response to GM-CSF.


OBJECTIVE
We sought to determine the effect of Pin1 inhibition on pulmonary eosinophilia after allergen challenge.


METHODS
The Pin1 inhibitor juglone (5-hydroxy-1,4-naphthoquinone) was administered to allergen-sensitized and allergen-challenged Brown Norway rats. Bronchoalveolar lavage fluid and lungs were assessed for inflammation, cytokine expression, and Pin1 activity.


RESULTS
Juglone-treated rats showed a dramatic reduction (approximately 75%) in bronchoalveolar lavage fluid and pulmonary eosinophilia but no change in lymphocyte, monocyte/macrophage, or neutrophil numbers. GM-CSF and IL-5 expression were also significantly reduced, whereas Pin1-independent cytokines, such as eotaxin or IL-4, as well as housekeeping mRNAs and proteins, including actin, were unaffected by juglone. The eosinophils present in the lung in juglone-treated rats showed significantly greater apoptosis.


CONCLUSIONS
These data suggest that in vivo Pin1 blockade attenuates GM-CSF and IL-5 production and can selectively reduce eosinophilic allergic inflammation.


CONCLUSIONS
Eosinophils can be selectively reduced by Pin1 blockade, despite allergen challenge.
Esnault
Stephane
S
Waisman Center for Developmental Disabilities, Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
Rosenthal
Louis A
LA
Shen
Zhong-Jian
ZJ
Sedgwick
Julie B
JB
Szakaly
Renee J
RJ
Sorkness
Ronald L
RL
Malter
James S
JS
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015848:Interleukin-5 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009285:Naphthoquinones / Q000494:pharmacology; D011657:Pulmonary Eosinophilia / Q000276:immunology*; D051381:Rats; D011919:Rats, Inbred Strains; D012130:Respiratory Hypersensitivity / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D015848:Interleukin-5; D009285:Naphthoquinones; C414604:PDZD2 protein, rat; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C005134:juglone