Human 60-kDa heat-shock protein: A danger signal to the innate immune system

Mammalian 60-kDa heat-lock protein (hsp60) is a key target of T cell and Ab responses in chronic inflammation or atherosclerosis, We show in this stud y that human hsp60 is also an Ag recognized by cells of the innate immune s ystem, such as macrophages, Both mouse and human macrophages respond to con tact with exogenous human hsp60 with rapid release of TNF-alpha; mouse macr ophages in addition produce nitric oxide. The proinflammatory macrophage re sponse is hsp60 dose dependent and similar in kinetics and extent to LPS st imulation. Human hsp60 was found to synergize with IFN-gamma in its proinfl ammatory activity. Finally, human hsp60 induces gene expression of the Th1- promoting cytokines IL-12 and IL-15. These findings identify autologous hsp 60 as a danger signal for the innate immune system, with important implicat ions For a role of local hsp60 expression/release in chronic Th1-dependent tissue inflammation.