Proapoptotic chemotherapeutic drugs induce noncanonical processing and release of IL-1β via caspase-8 in dendritic cells.
The identification of noncanonical (caspase-1-independent) pathways for IL-1β production has unveiled an intricate interplay between inflammatory and death-inducing signaling platforms. We found a heretofore unappreciated role for caspase-8 as a major pathway for IL-1β processing and release in murine bone marrow-derived dendritic cells (BMDC) costimulated with TLR4 agonists and proapoptotic chemotherapeutic agents such as doxorubicin (Dox) or staurosporine (STS). The ability of Dox to stimulate release of mature (17-kDa) IL-1β was nearly equivalent in wild-type (WT) BMDC, Casp1(-/-)Casp11(-/-) BMDC, WT BMDC treated with the caspase-1 inhibitor YVAD, and BMDC lacking the inflammasome regulators ASC, NLRP3, or NLRC4. Notably, Dox-induced production of mature IL-1β was temporally correlated with caspase-8 activation in WT cells and greatly suppressed in Casp8(-/-)Rip3(-/-) or Trif(-/-) BMDC, as well as in WT BMDC treated with the caspase-8 inhibitor, IETD. Similarly, STS stimulated robust IL-1β processing and release in Casp1(-/-)Casp11(-/-) BMDC that was IETD sensitive. These data suggest that TLR4 induces assembly of caspase-8-based signaling complexes that become licensed as IL-1β-converting enzymes in response to Dox and STS. The responses were temporally correlated with downregulation of cellular inhibitor of apoptosis protein 1, suggesting suppressive roles for this and likely other inhibitor of apoptosis proteins on the stability and/or proteolytic activity of the caspase-8 platforms. Thus, proapoptotic chemotherapeutic agents stimulate the caspase-8-mediated processing and release of IL-1β, implicating direct effects of such drugs on a noncanonical inflammatory cascade that may modulate immune responses in tumor microenvironments.
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
Christina
C
Antonopoulos
Caroline
C
El Sanadi
William J
WJ
Kaiser
Edward S
ES
Mocarski
George R
GR
Dubyak
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000172:deficiency / Q000235:genetics; D053471:Caspases, Initiator; D003598:Cytoskeletal Proteins / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D003598:Cytoskeletal Proteins; D051034:Inhibitor of Apoptosis Proteins; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004317:Doxorubicin; C494834:Birc2 protein, mouse; D044767:Ubiquitin-Protein Ligases; C101136:Casp4 protein, mouse; D053181:Caspase 8; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1; D019311:Staurosporine