| Research Abstract |
IL-18 was discovered as IFN-γ inducing factor (IGIF), and plays important roles in NK cell activation. IL-18 also induces proinflammatory cytokines, chemokines, T helper 2 (Th2) cytokine (e.g. IL-4, IL-13), IgE and IgG1 production. The combination of IL-18 plus IL-2 or IL-12 upregulates IFN-γ gene expression, NK cytotoxicity, and has synergistic anti-tumor activity in vitro and in vitro. Here we report that daily administration of IL-18 with IL-2, but not IL-18 or IL-2 alone induces lethal lung injury in normal mice, but not IL-18Rα (IL-1R related protein) deficient (-/-) mice. Marked interstitial infiltration of lymphocytes, composed mainly of NK cells was found in the lungs of IL-18/IL-2-treated mice. Increased cytokine and chemokine levels were observed in the sera and lungs of IL-18/IL-2-treated mice. Administration of IL-I8/TL-2 was also lethal to mice treated with a metalloproteinase inhibitor, which inhibited TNF-α and FasL release. While IFN-γ (-/-) mice were partially resistant to the treatment, IL-4 (-/-), IL-4/IL-13 (-/-) and Stat6 (-/-) mice were sensitive to the IL-18/IL-2 indicating these genes were not involved in the host response. The lethal effect by IL-I8/IL-2 was completely eliminated in SCID mice pretreated with anti-asialo-GM1 Ab and normal mice pretreated with anti-NK1.1, but not anti-CD4 or anti-CD8 mAb. These results suggest that specific cytokines, chemokines and NK cells are involved in the pathogenesis of interstitial pneumonia. These results suggest that the clinical use of this interleukin may result in unexpected physiological consequences.
|
