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Chain1
*
Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262; and
Laboratory of Experimental Immunology, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702
IL-18 and IL-12 are major IFN-
-inducing cytokines but the unique
synergism of IL-18 and IL-12 remains unclear. In the human NK cell line
NKO, IL-18R
, and IL-18R
are expressed constitutively but IL-18
did not induce IFN- unless IL-12 was present. COS-1 fibroblasts,
which produce the chemokine IL-8 when stimulated by IL-1 or TNF-,
do not respond to IL-18, despite abundant expression of the IL-18R
chain. COS-1 cells lack expression of the IL-18R chain. The
IL-18R cDNA was cloned from a human T-B lymphoblast cDNA library and
COS-1 cells were transiently transfected with the IL-18R 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 chain, however, prevented IL-18 responsiveness
in COS-1 cells transfected with the IL-18R chain, suggesting that
both chains be functional. In NKO cells and PBMC, IL-12 increased
steady-state mRNA levels of IL-18R and IL-18R; the production of
IFN- corresponded to IL-12-induced IL-18R and IL-18R chains.
We conclude that functional reconstitution of the IL-18R 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- production is, in part, due to IL-12 up-regulation of both
IL-18R and IL-18R chains, although postreceptor events likely
contribute to IFN- production.
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