Invasive candidiasis stimulates hepatocyte and monocyte production of active transforming growth factor beta

Candida albicans is an opportunistic fungal pathogen and a major cause of m orbidity and mortality in patients with compromised immune function. The cy tokine response to tissue invasion by C. albicans can influence the differe ntiation and function of lymphocytes and other mononuclear cells that are c ritical components of the host response. While the production of transformi ng growth factor beta (TGF-beta) has been documented in mice infected with C. albicans and is known to suppress phagocyte function, the cellular sourc e and role of this cytokine in the pathogenesis of systemic candidiasis are not well understood. We have investigated the source of production of TGF- beta by immunohistochemical studies in tissue samples from patients with an uncommon complication of lymphoreticular malignancy, chronic disseminated candidiasis (CDC), and from a neutropenic-rabbit model of CDC. Liver biopsy specimens from patients with documented CDC demonstrated intense staining for extracellular matrix-associated TGF-beta1 within inflammatory granuloma s, as well as staining for TGF-beta1 and TGF-beta3 within adjacent hepatocy tes. These results correlate with the immunolocalization of TGF-beta3 obser ved in livers of infected neutropenic rabbits, using a neutralizing antibod y that recognizes the mature TGF-beta protein. Human peripheral blood monoc ytes incubated with C. albicans in vitro release large amounts of biologica lly active TGF-beta1. The data demonstrate that local production of active TGF-betas by hepatocytes and by infected mononuclear cells is a component o f the response to C. albicans infection that most probably contributes to d isease progression in the immunocompromised host.