Resistance to Fas-mediated apoptosis in human lung fibroblast.
The current authors have demonstrated previously that epithelial cell apoptosis, induced by the Fas-Fas ligand pathway, might be involved in fibrosing lung diseases. Whereas lung epithelial cells are sensitive to the Fas-mediated apoptosis, lung fibroblasts may be resistant to Fas-mediated apoptosis and replace damaged epithelial cells. The WI-38 lung fibroblast cell line and primary lung fibroblasts were used to examine the resistant to Fas-mediated apoptosis and the association of anti-apoptotic proteins with this resistance. The administration of agonistic anti-Fas antibody (CH-11) or cycloheximide alone did not induce apoptosis, whereas the co-administration of CH-11 with cycloheximide induced apoptosis in WI-38 cells, in which caspase-8 and -3, but not -9, were activated, and X chromosome-linked inhibitor of apoptosis (ILP) and FLICE-like inhibitor protein (FLIP(L)), but not bcl-xL and bcl-2, were remarkably down regulated. Primary lung fibroblasts were also resistant to Fas-mediated apoptosis, and ILP and FLIP appeared to be involved in this resistance. Furthermore, the results of immunohistochemistry demonstrated that fibroblasts expressed ILP and FLIP(L) proteins in lung tissues from patients with idiopathic pulmonary fibrosis. These results suggest that anti-apoptotic proteins such as X chromosome-linked inhibitor of apoptosis and FLICE-like inhibitor protein may play an important role in preventing Fas-mediated apoptosis in lung fibroblasts, and participate in the development of pulmonary fibrosis.
Tanaka
T
T
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yoshimi
M
M
Maeyama
T
T
Hagimoto
N
N
Kuwano
K
K
Hara
N
N
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002460:Cell Line / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000032:analysis; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D008875:Middle Aged; D011506:Proteins / Q000032:analysis; D011658:Pulmonary Fibrosis / Q000473:pathology / Q000503:physiopathology*; D019014:fas Receptor / Q000032:analysis* / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D019014:fas Receptor