Interferon-gamma inducing factor (IGIF) is a recently identified cytokine also called interleukin-1gamma (IL-1gamma) or interleukin-18 (IL-18). Its biological activity is pleiotropic, and, so far, it has been shown to induce interferon-gamma production in Th1 cells, to augment the production of granulocyte-macrophage-CSF, and to decrease that of interleukin-10 (IL-10). We first detected newly synthesized IGIF mRNA by differential display in the adrenal gland of reserpine-treated rats and then isolated two transcripts by reverse transcription polymerase chain reaction. They were identified as rat IGIF on the basis of the high homology with mouse: 91% at both the nucleotide and the amino acid level. Subsequently, we investigated the effects of stress on IGIF mRNA levels and found that acute cold stress strongly induced IGIF gene expression. In situ hybridization analysis showed that IGIF is synthesized in the adrenal cortex, specifically in the zona reticularis and fasciculata that produce glucocorticoids. The presence of IGIF mRNA was also detected in the neurohypophysis although induction by stress was not significant. Our results call for more attention to the role of the adrenal gland as a potential effector of immunomodulation and suggest that IGIF itself might be a secreted neuroimmunomodulator and play an important role in orchestrating the immune system following a stressful experience.