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 syne rgism 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 respo nd to IL-18, despite abundant expression of the IL-18R alpha chain. COS-1 c ells lack expression of the IL-1R beta chain. The IL-18R beta cDNA was clon ed from a human T-B lymphoblast cDNA library and COS-1 cells were transient ly transfected with the IL-18R beta chain and a luciferase reporter. In tra nsfected COS-I cells, IL-18 induced IL-8 and luciferase in the absence of I L-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 a ctivity of IL-18-induced IL-8 in fibroblasts. The synergism of IL-18 plus I L-12 for IFN-gamma production is, in part, due to IL-12 up-regulation of bo th IL-18R alpha and IL-18R beta chains, although postreceptor events likely contribute to IFN-gamma production.