Peptides may play a physiologic role in regulating immune responses and in triggering a variety of cellular events that modify the sensitivity of cells in the periphery. Neurotensin (NT) is present in the lung and it has been shown to bind to mouse peritoneal macrophages and influence their phagocytic ability. In this study, the effect of NT on the production of IL-1 by rat alveolar macrophages (AM) has been investigated. Although NT did not stimulate the release of IL-1 or increase the apparent intracellular pool of IL-1 when incubated with AM, there was significant cell changes, such as increased adherence, spreading, and altered shape. Furthermore, when AM were stimulated with LPS, both the intracellular and extracellular pools of IL-1 were significantly increased by NT. This effect was dose dependent and was observed at concentrations ranging from 10(-11) to 10(-6) M. NT did not modify the kinetics of LPS-induced IL-1 release nor the effects of a given suboptimal concentration of LPS. The release of IL-1 by various inducers, including muramyl dipeptide (MDP) and zymosan was also enhanced by NT, suggesting a general modulator role for this neuropeptide. When NT was added concomitantly with other potentiators of IL-1 production, such as IFN-gamma and leukotriene B4, no synergistic effect on IL-1 release was seen. Kinetics experiments showed that optimal enhancement of IL-1 production occurred when AM cultures were preincubated with NT before addition of MDP or when NT and MDP were present together at the initiation of the 24-h AM cultures. Taken together, our data suggest that NT acts early in the induction process of IL-1. Because IL-1 plays an important role both in the initiation of the immune response and in the local manifestations of inflammation, NT released in the vicinity of pulmonary blood vessels and the respiratory epithelium may modulate immunologically relevant responses in the lung microenvironment.