Interleukin-1 and tumor necrosis factor receptor signaling is not requiredfor bacteria-induced osteoclastogenesis and bone loss but is essential forprotecting the host from a mixed anaerobic infection

Bacterial infection causes significant morbidity, mediated in part by the u p-regulation of inflammatory cytokines. Cytokine induction is thought to st imulate osteolysis in conditions such as periodontal disease and otitis med ia. To establish the relative importance of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in mediating the response to a mixed anaerobic infect ion, we used an in vivo model in which the dental pulp was inoculated with six anaerobic pathogens, in mice with functional deletions of receptors to IL-1 (IL-IRI-/-), TNF (TNFRp55(-/-)-p75(-/-)), or both (TNFRp55(-/-)-IL-1RI (-/-)). Polymorphonuclear and mononuclear phagocyte recruitment occurred to the greatest extent in TNFRp55(-/-)-IL-1RI(-/-) mice, and to a lesser exte nt in IL-1RI(-/-) or TNFRp55(-/-)-p75(-/-) mice, and the least in wild-type mice, demonstrating that recruitment of these phagocytes is not dependent on IL-1 or TNF receptor signaling. A similar pattern was observed for bacte rial penetration into host tissue. Because it had recently been reported th at TNF played a critical role in mediating lipopolysaccharide-induced bone loss, we anticipated that mice with targeted deletions of TNFRp55(-/-) woul d have reduced osteoclastogenesis, Surprisingly, osteolytic lesion formatio n was greatest in animals lacking TNF and/or IL-1 receptors, These results indicate that IL-1 or TNF receptor signaling is not required for bacteria-i nduced osteoclastogenesis and bone loss, but does play a critical role in p rotecting the host against mixed anaerobic infections.