FK506 (tacrolimus) improves lung injury through inhibition of Fas-mediated inflammation.
OBJECTIVE
To investigate whether FK506 (tacrolimus) can inhibit Fas- or A23187-induced interleukin (IL)-8 expression and cell death in A549 human alveolar epithelial cells, plus Fas-mediated acute lung injury in vivo.


METHODS
Assays for IL-8, cell death, and caspase-3 activity were performed. A549 cells were treated with 25 micromol A23187 or 0.2 microg/ml agonistic anti-Fas antibody plus 5 ng/ml interferon-gamma (IFN-gamma). Tacrolimus was treated at 0.1-10 ng/ml. For in vivo experiment, agonistic anti-Fas antibody (Jo2) at 2.5 microg/g was intratracheally instilled into C57BL/6 mice. Neutrophils and protein contents in bronchoalveolar lavage (BAL) fluid were measured within 24 h of instillation. Mice were orally treated with 32 mg/kg of tacrolimus 24 h and 1 h prior to instillation.


RESULTS
Both Fas and A23187 caused significant IL-8 expression and cell death in A549 cells. Tacrolimus inhibited A23187-induced IL-8 expression alone while it protected all Fas-mediated responses. Mice instilled intratracheally with Jo2 at 2.5 microg/g had significant increases in neutrophils, protein contents in BAL fluid and in expression of chemoattractants for neutrophils. These increases were reversed by tacrolimus.


CONCLUSIONS
Tacrolimus serves as a therapeutic option for improving lung injury through inhibition of Fas-mediated inflammation.
Koshika
T
T
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka, 532-8514, Japan. tadatsura.koshika@jp.astellas.com
Masunaga
T
T
Hirayama
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000166:cytology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D016559:Tacrolimus / Q000494:pharmacology*; D019014:fas Receptor / Q000037:antagonists & inhibitors* / Q000502:physiology
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D016209:Interleukin-8; D012333:RNA, Messenger; D019014:fas Receptor; D000001:Calcimycin; D053148:Caspase 3; D016559:Tacrolimus