Abstract
Resident, non-immune cells express various pattern-recognition receptors and produce inflammatory cytokines in response to microbial antigens, during the innate immune response. Alveolar bone resorption is the hallmark of destructive periodontitis and it is caused by the host response to bacteria and their mediators present on the biofilm. The balance between the expression levels of receptor activator of nuclear factorkappa B ligand (RANKL) and osteoprotegerin (OPG) is pivotal for osteoclast differentiation and activity and has been implicated in the progression of bone loss in periodontitis. To assess the contribution of resident cells to the bone resorption mediated by innate immune signaling, we stimulated fibroblasts and osteoblastic cells with LPS from. Escherichia coli (TLR4 agonist), Porphyromonas gingivalis (TLR2 and -4 agonist), and interleukin-1 beta (as a control for cytokine signaling through Toll/IL-1receptor domain) in time-response experiments. Expression of RANKL and OPG mRNA was studied by RT-PCR, whereas the production of RANKL protein and the activation of p38 MAPK and NF-kB signaling pathways were analyzed by western blot. We used biochemical inhibitors to assess the relative contribution of p38 MAPK and NF-kB signaling to the expression of RANKL and OPG induced by TLR2, -4 and IL1β in these cells. Both p38 MAPK and NFkB pathways were activated by these stimuli in fibroblasts and osteoblasts, but the kinetics of this activation varied in each cell type and with the nature of the stimulation. E. coli LPS was a stronger inducer of RANKL mRNA in fibroblasts, whereas LPS from P. gingivalis downregulated RANKL mRNA in periodontal ligament cells but increased its expression in osteoblasts. IL-1β induced RANKL in both cell types and without a marked effect on OPG expression. p38 MAPK was more relevant than NF-kB for the expression of RANKL and OPG in these cell types.
Highlights
In the early 1950s, the mood-elevating effects of the monoamine oxidase inhibitors (MAOIs) were discovered serendipitously
When we analyzed the drug and placebo response for each type of drug, we found another surprise awaiting us
Based on their tolerability profile, the selective serotonin reuptake inhibitors (SSRIs) are a significant advancement over the tricyclic antidepressants (TCAs) for the treatment of depression
Summary
In the early 1950s, the mood-elevating effects of the monoamine oxidase inhibitors (MAOIs) were discovered serendipitously Further investigations of these compounds and the tricyclic antidepressants (TCAs) led to early theories relating brain chemistry and mood. TCAs nonselectively inhibit the reuptake of serotonin, norepinephrine, and dopamine into presynaptic storage vesicles in the brain. They are effective in treating depression, their effects on other receptor systems, including histaminic, cholinergic, adrenergic, and postsynaptic serotonin receptors unrelated to depression, led to the development of significant, often intolerable adverse effects that limited their use in clinical practice
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