TY - JOUR
T1 - Desiccating stress induces CD4 + T-cell-mediated Sjögren's syndrome-like corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway by interferon-γ
AU - Zhang, Xiaobo
AU - Chen, Wei
AU - De Paiva, Cintia S.
AU - Volpe, Eugene A.
AU - Gandhi, Niral B.
AU - Farley, William J.
AU - Li, De Quan
AU - Niederkorn, Jerry Y.
AU - Stern, Michael E.
AU - Pflugfelder, Stephen C.
PY - 2011/10
Y1 - 2011/10
N2 - We investigated the role of CD4 + T-cellproduced interferon (IFN)-γ on corneal epithelial apoptosis in a murine desiccating stress (DS) model that resembles Sjögren's syndrome. The DS model was generated in C57BL/6 (B6) and B6 IFN-γknockout (B6γKO) mice. Adoptive transfer of CD4 + T cells from DS-exposed donor to recombination activating gene (RAG)-1 -/- recipient mice and topical neutralization of IFN-γ were performed to determine whether IFN-γ produced by pathogenic CD4 + T cells promotes corneal epithelial apoptosis. Apoptosis in corneal epithelia was assessed by evaluating the expression and activity of caspases 3, 8, and 9. The activation of caspase-8 mediated increased corneal epithelial apoptosis in B6 mice after DS, and this was exacerbated by subconjunctival IFN-γ injection. B6γKO mice were resistant to DS-induced apoptosis; however, B6γKO mice receiving IFN-γ developed apoptosis similar to that observed in B6 wild-type mice. Adoptive transfer of CD4 + T cells from donors subjected to DS increased corneal epithelial apoptosis via activation of caspase-8 in recipients, similar to that in the donor mice. Topical neutralization of IFN-γ in adoptive transfer recipients decreased corneal epithelial apoptosis. DS, IFN-γ administration, or CD4 + T-cell adoptive transfer had no effect on the expression and activation of the intrinsic apoptosis mediator, caspase-9. CD4 + T-cellproduced IFN-γ plays a pivotal role in DS-induced corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway.
AB - We investigated the role of CD4 + T-cellproduced interferon (IFN)-γ on corneal epithelial apoptosis in a murine desiccating stress (DS) model that resembles Sjögren's syndrome. The DS model was generated in C57BL/6 (B6) and B6 IFN-γknockout (B6γKO) mice. Adoptive transfer of CD4 + T cells from DS-exposed donor to recombination activating gene (RAG)-1 -/- recipient mice and topical neutralization of IFN-γ were performed to determine whether IFN-γ produced by pathogenic CD4 + T cells promotes corneal epithelial apoptosis. Apoptosis in corneal epithelia was assessed by evaluating the expression and activity of caspases 3, 8, and 9. The activation of caspase-8 mediated increased corneal epithelial apoptosis in B6 mice after DS, and this was exacerbated by subconjunctival IFN-γ injection. B6γKO mice were resistant to DS-induced apoptosis; however, B6γKO mice receiving IFN-γ developed apoptosis similar to that observed in B6 wild-type mice. Adoptive transfer of CD4 + T cells from donors subjected to DS increased corneal epithelial apoptosis via activation of caspase-8 in recipients, similar to that in the donor mice. Topical neutralization of IFN-γ in adoptive transfer recipients decreased corneal epithelial apoptosis. DS, IFN-γ administration, or CD4 + T-cell adoptive transfer had no effect on the expression and activation of the intrinsic apoptosis mediator, caspase-9. CD4 + T-cellproduced IFN-γ plays a pivotal role in DS-induced corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway.
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U2 - 10.1016/j.ajpath.2011.06.030
DO - 10.1016/j.ajpath.2011.06.030
M3 - Article
C2 - 21843497
AN - SCOPUS:80053231190
SN - 0002-9440
VL - 179
SP - 1807
EP - 1814
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -