Orientia tsutsugamushi (OT) is a Gram-negative obligate intracellular bacterium which causes scrub typhus. OT survives and replicates inside macrophages, which are potent effector cells to kill the pathogens. Hyper-production of cytokines is associated with host susceptibility by OT infection. The immunoregulatory mechanisms in macrophages in response to OT are still unknown. We examined the dose effect of OT (TW-1 strain) infection on human THP-1 macrophage. In low dose infection (ratio of bacteria to macrophages was 2:1), OT induced IL-10 production to ten-fold and lowered the TNF-α, IL-1β and IL-6 secretion in macrophages time dependently. In high dose infection (ratio of bacteria to macrophages was 100:1), OT induced IL-10 production to four-fold and increased the TNF-α, IL-1β and IL-6 secretion in macrophages time dependently. When macrophages pretreated with IL-10 and then exposed to high dose infection, the TNF-α production was suppressed and cell survival rate increased. IL-10 production in macrophage is mainly via the ERK signaling pathway. When macrophages pretreated with PD98059 to block ERK pathway and then exposed to low dose infection, there was no IL-10 but high TNF-α production. miR155 was upregulated by a time dependent and dose dependent way which was 10-fold increase in high dose infection compared to 4-fold increase in low dose infection. When macrophages pretreated with IL-10, the miR155 response to high dose infection was abolished and TNF-α production was burst increased. When macrophages pretreated with anti-miR155, TNF-α production was increased and no IL-10 production during high dose infection. miR155 and IL-10 play the key roles in the immunoregulation of OT-infected macrophages. Dysregulation of miR155 or IL-10 may contribute to the host susceptibility to OT infection.
Date:
2013-05
Relation:
Journal of Investigative Dermatology. 2013 May;133:S204.
