Interleukin-10 as a negative regulator of interferon-mediated immunity in chlamydial infections

IFN-induced indoleamine 2,3-dioxygenase (IDO) inhibits intracellular chlamydiae by restricting the availability of tryptophan required for chlamydial growth. The pro-inflammatory cytokines that synergistically enhance IDO activity, IL-1beta and TNF-alpha, are produced by macrophages during in vitro chlamydial infections. These cytokines may be involved in the intensive inflammatory responses at sites of infection. However, asymptomatic infection occurs in 70-90% of infected patients, suggesting that antagonistic cytokines might be generated during the immune response in vivo. Interleukin-10 is an anti-inflammatory cytokine with potent immunomodulatory effects, including the inhibition of cytokine production. If IL-10 is produced during a chlamydial infection, it might inhibit the production of pro-inflammatory cytokines capable of up-regulating anti-chlamydial IDO activity. The purpose of this study was to evaluate the effectiveness of IL-10 production as a mechanism by which chlamydiae evade the effects of IFN-gamma. It was found that IL-10 treatment of macrophage cultures inhibited the production of IFN-alpha, IL-1beta and TNF-alpha as well as the induction of IDO activity in response to chlamydial infection in a concentration-related manner. IL-1beta and TNF-alpha were detected by 24 h after exposure to UV-inactivated Chlamydophila psittaci and live Chlamydia trachomatis, whereas IL-10 was detected at approximately 48 h after exposure to chlamydiae. The mechanism of IL-10 production in response to chlamydial infection was explored. It was found that IL-10 production from macrophages exposed to chlamydiae was dependent upon endogenous production of IL-1beta and TNF-alpha. Since UV-inactivated C. psittaci and C. trachomatis were unable to replicate in macrophages, involvement of chlamydiae-Toll like receptor 2 (TLR2) and 4 (TLR4) interaction on IL-1beta and TNF-alpha production was explored. Endogenous production of IL-1beta and TNF-alpha were initiated following the interaction between Chlamydia and TLR2 and TLR4 on the surface of macrophages. These results indicate that Chlamydia-TLR interaction stimulates a cascade of cytokine production capable of either up-regulating or down-regulating IFN-gamma-induced IDO activity. Overall this study suggests that IL-10 produced following Chlamydia-TLR interaction may inhibit the induction of effective immunological responses by inhibiting pro-inflammatory cytokine production by macrophages.