Invasive Candidiasis Stimulates Hepatocyte and Monocyte Production of Active Transforming Growth Factor β

Candida albicans is an opportunistic fungal pathogen and a major cause of morbidity and mortality in patients with compromised immune function. The cytokine response to tissue invasion by C. albicans can influence the differentiation and function of lymphocytes and other mononuclear cells that are critical components of the host response. While the production of transforming growth factor β (TGF-β) has been documented in mice infected with C. albicans and is known to suppress phagocyte function, the cellular source and role of this cytokine in the pathogenesis of systemic candidiasis are not well understood. We have investigated the source of production of TGF-β 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-β1 within inflammatory granulomas, as well as staining for TGF-β1 and TGF-β3 within adjacent hepatocytes. These results correlate with the immunolocalization of TGF-β observed in livers of infected neutropenic rabbits, using a neutralizing antibody that recognizes the mature TGF-β protein. Human peripheral blood monocytes incubated with C. albicans in vitro release large amounts of biologically active TGF-β1. The data demonstrate that local production of active TGF-βs by hepatocytes and by infected mononuclear cells is a component of the response to C. albicans infection that most probably contributes to disease progression in the immunocompromised host.