IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T cells

Int Immunol. 2000 Feb;12(2):151-60. doi: 10.1093/intimm/12.2.151.


IL-18 is a proinflammatory cytokine that plays an important role in NK cell activation and T(h)1 response. IL-18 has a structural homology to IL-1, particularly IL-1beta. IL-18R, composed of IL-1R-related protein (IL-18Ralpha) and IL-1R accessory protein-like (IL-18Rbeta), belongs to the IL-1R family. Furthermore, IL-18R at least partly shares the signal transducing system with IL-1R. Thus, the IL-18-IL-18R system has a striking similarity to the IL-1-IL-1R system. For this reason, we regarded it important to investigate whether, like IL-18, IL-1beta synergizes with IL-12 in inducing IFN-gamma production from human T cells and plays an important role in the T(h)1 response. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R. Then, IL-12-stimulated T cells responded to IL-18 or IL-1beta by their proliferation and IFN-gamma production, although levels of IL-1beta-induced responses were lower. CD4(+)CD45RA(+) T cells, although they constitutively expressed IL-18Rbeta mRNA, did not express IL-18Ralpha mRNA. Phytohemagglutinin (PHA) stimulation alone induced IL-18Ralpha mRNA without affecting the expression of IL-18Rbeta mRNA. T(h)1-inducing conditions (PHA, IL-12 and anti-IL-4) further increased this expression. We also show that T(h)1 cells but not T(h)2 cells have increased expression of IL-18R and IL-1R, and produce IFN-gamma in response to IL-18 and/or IL-1beta.

MeSH terms

  • Drug Synergism
  • Gene Expression Regulation
  • Humans
  • Interferon-gamma / biosynthesis*
  • Interleukin-1 / immunology
  • Interleukin-1 / metabolism
  • Interleukin-1 / pharmacology*
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Interleukin-12 / pharmacology*
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism
  • Interleukin-18 / pharmacology*
  • Interleukin-18 Receptor alpha Subunit
  • Lymphocyte Activation / drug effects
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-18
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Th1 Cells / immunology
  • Th2 Cells / immunology


  • IL18R1 protein, human
  • Interleukin-1
  • Interleukin-18
  • Interleukin-18 Receptor alpha Subunit
  • Receptors, Interleukin
  • Receptors, Interleukin-18
  • Interleukin-12
  • Interferon-gamma