Essential role for caspase-8 in Toll-like receptors and NFkappaB signaling.
In addition to its pro-apoptotic function in the death receptor pathway, roles for caspase-8 in mediating T-cell proliferation, maintaining lymphocyte homeostasis, and suppressing immunodeficiency have become evident. Humans with a germline point mutation of CASPASE-8 have multiple defects in T cells, B cells, and NK cells, most notably attenuated activation and immunodeficiency. By generating mice with B-cell-specific inactivation of caspase-8 (bcasp8(-/-)), we show that caspase-8 is dispensable for B-cell development, but its loss in B cells results in attenuated antibody production upon in vivo viral infection. We also report an important role for caspase-8 in maintaining B-cell survival following stimulation of the Toll-like receptor (TLR)2, -3, and -4. In response to TLR4 stimulation, caspase-8 is recruited to a complex containing IKKalphabeta, and its loss resulted in delayed NFkappaB nuclear translocation and impaired NFkappaB transcriptional activity. Our study supports dual roles for caspase-8 in apoptotic and nonapoptotic functions and demonstrates its requirement for TLR signaling and in the regulation of NFkappaB function.
Lemmers
Bénédicte
B
Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
Salmena
Leonardo
L
Bidère
Nicolas
N
Su
Helen
H
Matysiak-Zablocki
Elzbieta
E
Murakami
Kiichi
K
Ohashi
Pamela S
PS
Jurisicova
Andrea
A
Lenardo
Michael
M
Hakem
Razqallah
R
Hakem
Anne
A
D000818:Animals; D053181:Caspase 8 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D018353:Rhabdoviridae Infections / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014721:Vesicular stomatitis Indiana virus; D019014:fas Receptor / Q000502:physiology
D008070:Lipopolysaccharides; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019014:fas Receptor; D053181:Caspase 8