Little is known about the detail of the immune response during infection of pigs with Mycoplasma hyopneumoniae (Mhp). To further understand this important porcine pathogen, we examined the interleukin-18 (IL- 18) response in experimentally infected piglets. We found that large amounts of IL-18 were produced in the bronchoalveolar lavage fluids (BALF) of pigs experimentally infected with Mhp. However, the concentration of interferon-gamma (IFN-gamma) in the same BALF was negatively correlated with that of IL-18. The antibody response against Mhp was found to be associated with the IL-18 concentration in the BALF. Immunohistochemical staining revealed that both IL-18 and IL-18 receptor alpha chain (IL-18Ralpha) were present in macrophages and plasma cells in the lungs of Mhp-infected pigs. Lung mononuclear cells isolated from pneumonic lesions secreted IL-18 and prostaglandin E(2) (PGE(2)) in vitro, and PGE(2) production was enhanced by stimulation with IL-18. These results indicate that IL-18 produced in the pig lung contributes to the development of innate and acquired immune responses against Mhp as a proinflammatory cytokine rather than as an IFN-gamma-inducing factor and may be involved in immunomodulation in pigs.