Accessory protein-like is essential for IL-18-mediated signaling.
IL-18 is an essential cytokine for both innate and adaptive immunity. Signaling by IL-18 requires IL-18Ralpha, which binds specifically to the ligand and contains sequence homology to IL-1R and TLRs. It is well established that IL-1R signaling requires an accessory cell surface protein, AcP. Other accessory proteins also exist with roles in regulating TLR signaling, but some have inhibitory functions. An AcP-like molecule (AcPL) has been identified with the ability to cooperate with IL-18Ralpha in vitro; however, the physiological function of AcPL remains unknown. In this study, we demonstrate that IL-18 signals are abolished in AcPL-deficient mice and cells. Splenocytes from mutant mice fail to respond to IL-18-induced proliferation and IFN-gamma production. In particular, Th1 cells lacking AcPL fail to produce IFN-gamma in response to IL-18. AcPL-deficient neutrophils also fail to respond to IL-18-induced activation and cytokine production. Furthermore, AcPL is required for NK-mediated cytotoxicity induced by in vivo IL-18 stimulation. However, AcPL is dispensable for the activation or inhibition of IL-1R and the various TLR signals that we have examined. These results suggest that AcPL is a critical and specific cell surface receptor that is required for IL-18 signaling.
Cheung
Heidi
H
Advanced Medical Discovery Institute/Campbell Family Institute for Breast Cancer Research, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Chen
Nien-Jung
NJ
Cao
Zhaodan
Z
Ono
Nobuyuki
N
Ohashi
Pamela S
PS
Yeh
Wen-Chen
WC
D000818:Animals; D001947:Breeding; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018390:Gene Targeting; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000008:administration & dosage / Q000502:physiology*; D053728:Interleukin-18 Receptor beta Subunit; D007694:Killer Cells, Natural / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000502:physiology; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000502:physiology; D011995:Recombination, Genetic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors
D016207:Cytokines; C501223:IL18rap protein, mouse; D020382:Interleukin-18; D053728:Interleukin-18 Receptor beta Subunit; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D007371:Interferon-gamma