THE mechanism underlying the differentiation of CD4(+) T cells into functionally distinct subsets (Th1 and Th2) is incompletely understood(1-3), and hitherto unidentified cytokines may be required for the functional maturation of these cells(4). Here we report the cloning of a recently identified IFN-gamma-inducing factor (IGIF) that augments natural killer (NK) activity in spleen cells(5,6). The gene encodes a precursor protein of 192 amino acids and a mature protein of 157 amino acids, which have no obvious similarities to any peptide in the databases. Messenger RNAs for IGIF and interleukin-12 (IL-12) are readily detected in Kupffer cells and activated macrophages. Recombinant IGIF induces IFN-gamma more potently than does IL-12, apparently through a separate pathway. Administration of anti-IGIF antibodies prevents liver damage in mice inoculated with Propionibacterium acnes and challenged with lipopolysaccharide, which induces toxic shock. IGIF may he involved in the development of Th1 cells and also in mechanisms of tissue injury in inflammatory reactions.