Interleukin-6 Deficiency Increases Inflammatory Bone Destruction

Abstract

ABSTRACT Periapical bone destruction occurs as a consequence of pulpal infection. In previous studies, we showed that interleukin-1 (IL-1) is the primary stimulator of bone destruction in this model. IL-6 is a pleiotropic cytokine that is induced in these infections and has both pro- and anti-inflammatory activities. In the present study, we determined the role of IL-6 in regulating IL-1 expression and bone resorption. The first molars of IL-6 knockouts (IL-6 −/− ) and wild-type mice were subjected to surgical pulp exposure and infection with a mixture of four common pulpal pathogens, including Prevotella intermedia , Fusobacterium nucleatum , Peptostreptococcus micros , and Streptococcus intermedius . Mice were killed after 21 days, and bone destruction and cytokine expression were determined. Surprisingly, bone destruction was significantly increased in IL-6 −/− mice versus that in wild-type mice (by 30%; P < 0.001). In a second experiment, the effects of chronic (IL-6 −/− ) IL-6 deficiency and short-term IL-6 deficiency induced by in vivo antibody neutralization were determined. Both IL-6 −/− (30%; P < 0.001) and anti-IL-6 antibody-treated mice (40%; P < 0.05) exhibited increased periapical bone resorption, compared to wild-type controls. The increased bone resorption in IL-6-deficient animals correlated with increases in osteoclast numbers, as well as with elevated expression of bone-resorptive cytokines IL-1α and IL-1β, in periapical lesions and with decreased expression of the anti-inflammatory cytokine IL-10. These data demonstrate that endogenous IL-6 expression has significant anti-inflammatory effects in modulating infection-stimulated bone destruction in vivo.