The concentration of C-reactive protein (CRP) increases in human plasma up to a thousandfold during inflammatory states. Because tissue macrophages have been shown to have receptors for CRP, the question arises of whether these cells may respond to increased local concentrations of CRP by producing cytokines capable of participating in the inflammatory response. Accordingly, we examined the capacity of alveolar macrophages--relatively accessible human macrophages--to produce interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) in response to CRP. We found that production of IL-1 alpha, IL-1 beta, and TNF-alpha, as measured by bioassay and immunoassay, increased in a dose-dependent manner after stimulation by CRP and that the levels of the respective mRNAs analyzed by Northern blot increased proportionally. These findings suggest that one of the functions of CRP may be to stimulate the production of IL-1 and TNF by macrophages at inflammatory sites where alterations of capillary permeability combined with an increased serum level lead to enhanced local concentrations of this acute-phase protein.