Classes reonine residues. Of the four distinct classes of MAP kinases described to date in mammals, p38, c Jun N terminal activated kinases and extracellular activated kinases are the PHA-680632 most studied. Downstream substrates of MAP kinases include a variety of transcription factors, RNA binding proteins and other kinases that are involved in regulation of gene expression by transcriptional, post transcriptional, translational and post translational mechanisms. This implies that therapeutic modulation of signaling pathways can affect various genes, depending not only on the pathway but also on the relative position targeted for inhibition in the signaling cascade. Interestingly, the proteins comprising many of the signaling pathways are much conserved among different species of organisms indicating their fundamental role in many essential physiological processes.
Some of these signaling pathways have also a relevant role in diverse pathological conditions, demonstrating their multivalency. For instance, the p38 MAPK pathway was originally described as critically important to signal stress, inflammatory and infectious stimuli, but it is also involved in the control of fundamental processes including cell proliferation, differentiation and migration. Nevertheless, many reports indicate its relevance and/or potential therapeutic application in disease processes that involves inflammation and immunity, including rheumatoid arthritis, ischemic heart disease, allergies, chronic obstructive pulmonary diseases, Alzheimer,s disease and cancer.
Surprisingly, in spite of evidence indicating a role of p38 MAPK in all these diseases, there is a relative paucity of information regarding its role in oral inflammation related conditions including temporo mandibular joint disorders, chronic oral pain and inflammatory changes of the oral mucosa. Interest in its role in chronic inflammatory periodontal diseases has occurred only in the past few years. Our lab group has shown the relevance of p38 MAPK for the regulation of expression of pro inflammatory cytokines and enzymes induced by inflammatory and infectious signals in vitro, including IL 6, MMP 13 and RANKL in periodontally relevant resident cells, such as fibroblasts and osteoblasts. This information obtained in vitro was also tested in in vivo models of periodontal disease and other inflammation associated diseases, as discussed later in this review.
Specifically in periodontal disease, in spite of a great deal of information available on the regulation and expression of inflammatory cytokines, there are only a few reports on the signaling pathways activated in vivo. Nuclear factor kappaB has been shown to be associated with increased periodontal disease severity. Our research group has found interesting differences on the activation of signaling pathways in two frequently used murine models of experimentally induced periodontal disease. In both the LPS injection model and the ligature model p38 and ERK MAP kinases, as well as NF κB was activated, but with different kinetics. On the other hand, activation of JAK STAT signaling was only observed with the ligature model. The cytokine profile associated with periodontal disease in vivo varies and includes both Th1 and Th2 type responses. IL 1, IL 1, IL 8 and TNF mRNA w .