SUMMARY:To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in mycobacterial inflammation, IL-1 ␣/␤ double-knockout (KO) mice were produced. These mice were infected with either Mycobacterium tuberculosis H37Rv by the airborne route using an airborne infection apparatus, and their capacities to control mycobacterial growth, granuloma formation, cytokine, and nitric oxide (NO) production were examined. The IL-1 ␣/␤ mice developed significantly larger (p Ͻ 0.01) granulomatous, but not necrotic, lesions in their lungs than wild-type (WT) mice after infection with H37Rv. Inflammatory lesions, but not granulomas, were observed in spleen and liver tissues from both IL-1 ␣/␤ KO and wild-type mice. Granulomatous lesion development in IL-1 ␣/␤ KO mice was not significantly inhibited by treatment with exogenous recombinant IL-1␣/␤. Compared with wild-type mice, splenic IFN-␥ and IL-12 levels were within the normal range. NO production by cultured alveolar macrophages from IL-1 ␣/␤ KO mice was lower than in wild-type mice but were increased by the addition of recombinant IL-1 ␣/␤. Our data clearly indicate that IL-1 is important for the generation of early-phase protective immunity against mycobacterial infection. (Lab Invest 2000, 80:759-767).