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 IL1ß 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-1ß 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.

Immunology has made tremendous progress more than a half-century after Burnets clonal selection theory was published, but there are still more questions than answers. What is the function of the immune system, given that invertebrates have lived without one for millions of years, although they are also susceptible to infections and tumors? On the other hand, the emergence of the immune system in evolution did not deliver higher animals from either infections or cancer. The concept of linked functions is an attempt at answering these and other related questions. The concept assumes that the evolutionary origin of the immune system is related to a primary nonimmune function rather than to self/ nonself recognition. However, the mechanisms used to fulfill this function proved to be a suitable basis for immune recognition, which, according to the concept, occurs at the level of receptor-bearing immune cells rather than receptors themselves. Since cross-reactivity is a common phenomenon, it is assumed that specific combinations of antigenic determinants, rather than determinants per se, serve as recognition criteria, antigen processing and MCH-II restriction being necessary steps of the immune recognition of these combinations. The new views on adaptive immunity suggest new approaches to preventing graft rejection and treating chronic infections and malignant tumors.