Vitronectin and fibronectin function as glucan binding proteins augmenting macrophage responses to Pneumocystis carinii

beta -glucans represent major structural components of fungal cell walls. We recently reported that Pneumocystis carinii R-glucans stimulate alveolar macrophages to release proinflammatory cytokines. Macrophage activation by beta -glucan is augmented by serum, implying the presence of circulating factors that interact with A-glucans and enhance their ability to stimulate macrophages. Using beta -glucan-enriched cell wall fractions from A carinii and Saccharomyces cerevisiae, two prominent proteins were precipitated from serum and demonstrated to be vitronectin (VN) and fibronectin (FN) by immune analysis. Preincubation of beta -glucan with VN or FN enhanced macrophage activation in response to this cell wall component. Because VN and FN accumulate in the lungs during A carinii pneumonia, we further investigated hepatic and pulmonary expression of VN and FN messenger RNA during infection. A carinii pneumonia in rodents is associated with increased hepatic expression of VN and FN as well as increased local expression of FN in the lung. Because interleukin (IL)-6 represents the major regulator of VN and FN expression during inflammatory conditions, we measured macrophage IL-6 release in response to stimulation with P. carinii R-glucan. Stimulation of macrophages with P. carinii beta -glucan induced significant release of IL-6. Elevated concentrations of IL-6 were noted in the blood of infected animals compared with uninfected control animals. These studies indicate that VN and FN bind to beta -glucan components of P. carinii and augment macrophage inflammatory responses. A carinii cell wall beta -glucan stimulates secretion of IL-6 by macrophages, thereby enhancing hepatic synthesis of both VN and FN, and lung synthesis of FN during pneumonia.