EXPRESSION OF HEAT SHOCK PROTEINS UPON THE ADDITION OF GELDANAMYCIN INCREASES PHAGOCYTOSIS OF IGG-OPSONIZED PARTICLES

Abstract

Cells are constantly subjected to an array of harmful conditions that trigger a widespread response to stress known as the shock response. Heat shock proteins (hsps), which are localized within the cell, are involved in damage repair after stress and further protection from subsequent insults. Recently, hsps have also been found in circulation after severe injury. The extracellular hsps have been proposed to constitute an "alert signal," playing a fundamental role in the modulation of immune response. Moreover, intracellular hsps, constitutive or inducible forms, could also regulate cellular functions important for the immune response. We have observed an increase in phagocytosis of IgGopsonized and non-opsonic particles upon incubation of murine macrophages (J774 cells) with geldanamycin (GA), which is a specific inhibitor of Hsp90 function. The effect of GA treatment of phagocytosis was reversed by the addition of transcription or translation blockers, indicating that gene expression was required. Thus, the increase in phagocytosis is likely due to the expression of hsps as a consequence of GA treatment. This assumption was confirmed by detecting the same increase in phagocytosis after heat shock. The increase in phagocytosis upon stress was not due to elevation of Fcγ receptors on the cell surface. However, it did correlate with an increase in intracellular calcium and a rapid polymerization of actin in proximity to the plasma membrane. The presence of F-actin could be detected even in the absence of foreign ligands, suggesting that hsps could prime macrophages toward phagocytic activity. These results demonstrate that the presence of hsps renders macrophages capable of internalizing pathogens in a highly efficient manner, which may have a tremendous impact on the response to injury and infection.