Functional reconstitution and regulation of IL-18 activity by the IL-18R beta chain.
IL-18 and IL-12 are major IFN-gamma-inducing cytokines but the unique synergism of IL-18 and IL-12 remains unclear. In the human NK cell line NKO, IL-18R alpha, and IL-18R beta are expressed constitutively but IL-18 did not induce IFN-gamma unless IL-12 was present. COS-1 fibroblasts, which produce the chemokine IL-8 when stimulated by IL-1 beta or TNF-alpha, do not respond to IL-18, despite abundant expression of the IL-18R alpha chain. COS-1 cells lack expression of the IL-18R beta chain. The IL-18R beta cDNA was cloned from a human T-B lymphoblast cDNA library and COS-1 cells were transiently transfected with the IL-18R beta chain and a luciferase reporter. In transfected COS-1 cells, IL-18 induced IL-8 and luciferase in the absence of IL-12 and independently of IL-1 and TNF. Ab against the IL-18R alpha chain, however, prevented IL-18 responsiveness in COS-1 cells transfected with the IL-18R beta chain, suggesting that both chains be functional. In NKO cells and PBMC, IL-12 increased steady-state mRNA levels of IL-18R alpha and IL-18R beta; the production of IFN-gamma corresponded to IL-12-induced IL-18R alpha and IL-18R beta chains. We conclude that functional reconstitution of the IL-18R beta chain is essential for IL-12-independent proinflammatory activity of IL-18-induced IL-8 in fibroblasts. The synergism of IL-18 plus IL-12 for IFN-gamma production is, in part, due to IL-12 up-regulation of both IL-18R alpha and IL-18R beta chains, although postreceptor events likely contribute to IFN-gamma production.
Kim
S H
SH
Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262, USA. soohyun.kim@uchsc.edu
Reznikov
L L
LL
Stuyt
R J
RJ
Selzman
C H
CH
Fantuzzi
G
G
Hoshino
T
T
Young
H A
HA
Dinarello
C A
CA
D000818:Animals; D019556:COS Cells / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005822:Genetic Vectors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D020382:Interleukin-18 / Q000378:metabolism / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D016328:NF-kappa B / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053724:Receptors, Interleukin-18; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C508572:IL18R1 protein, human; D007375:Interleukin-1; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D016328:NF-kappa B; D020033:Protein Isoforms; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma