Functional CD40 Expression Induced following Bacterial Infection of Mouse and Human Osteoblasts

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Abstract
Bacterially induced bone infections often result in significant local inflammatory responses which are coupled with loss of bone. However, the mechanisms necessary for the protective host response, or those responsible for pathogen-induced bone loss, are not clear. Recent evidence demonstrates that bacterially infected osteoblasts secrete chemokines and cytokines, suggesting that these cells may have an unappreciated role in supporting localized inflammation. In this study, mouse and human osteoblasts were investigated for their ability to express functional CD40 upon exposure to two important pathogens of bone, Staphylococcus aureus and Salmonella enterica serovar Dublin. Bacterial infection of cultured mouse or human osteoblasts resulted in increased CD40 mRNA and CD40 protein expression induced by either pathogen. Importantly, CD40 expression by osteoblasts was functional, as assessed by ligation of this molecule with recombinant, soluble CD154. CD40 activity was assessed by induction of interleukin-6 and granulocyte-macrophage colony-stimulating factor in osteoblasts following ligation. Cocultures of activated CD4+ T lymphocytes and osteoblasts could interact via CD40 and CD154, since an antibody against CD40 could block macrophage inflammatory protein-1α secretion. Taken together, these studies conclusively demonstrate that infected osteoblasts can upregulate expression of functional CD40 molecules which mediate cytokine secretion. This surprising result further supports the notion that bone-forming osteoblasts can directly interact with CD154-expressing cells (i.e., T lymphocytes) and can contribute to the host response during bone infection.