Inflammatory responses to pathogenic bacteria are essential for protection of the host and control of bacterial infection. However, inflammatory responses that are sustained in duration and intensity can be damaging to susceptible tissues. To limit the ferocity of inflammation and curtail possible tissue damage, a number of pathways exist that dampen the innate immune response. Our studies have focused on a tyrosine kinase of the Janus kinase (JAK) family, JAK3. We have found that that challenge with the periodontal pathogen P. gingivalis increases both the activation state and the amount of JAK3 in human monocytes and murine bone marrow derived macrophages. Moreover, JAK3 inhibition enhances the production of pro-inflammatory cytokines upon P. gingivalis stimulation, and concurrently diminishes levels of the anti-inflammatory cytokine IL-10. Thus, we have identified a novel role for JAK3 as a negative regulator of inflammation, and propose that stimulation of this endogenous anti-inflammatory pathway in the host will help limit or prevent P. gingivalis- induced tissue destruction. The specific hypothesis to be tested in this application is that P. gingivalis-modified JAK3 activation in innate immune cells directs negative regulation of inflammation, and ultimately controls alveolar bone loss, through dedicated downstream signaling pathways. We will challenge this hypothesis with three specific Aims: 1) To characterize JAK3 signaling pathways that control anti-inflammatory responses induced by P. gingivalis; 2) To functionally dissect P. gingivalis modification of JAK3 expression and activation in innate immune cells; 3) To determine the effect of JAK3 inhibition in vivo on inflammatory responses and the disease process induced by P. gingivalis using a mouse chamber model and bone loss model. Successful completion of these studies will define, for the first time, the host anti-inflammatory responses to P. gingivalis that flow through JAK3. In addition, this work will characterize an important, but relatively understudied, aspect of the overall host-P. gingivalis interaction, and increase our understanding both of the role of JAK3 in innate immune cells and of anti-inflammatory mechanisms in general. This work could be translated into the identification of novel targets for therapeutic intervention designed to enhance anti-inflammatory signaling and prevent or limit tissue destruction. Such an approach has relevance both for periodontal disease and for chronic inflammatory conditions in general.
To protect against bacterial infection our bodies mount an inflammatory response; however, this response must be regulated to prevent excessive inflammation and associated tissue damage. We have identified a host signaling protein called JAK3 that can dampen inflammatory responses to a gum disease causing organism. In this study we will characterize the role of JAK3 with the ultimate goal of designing means to stimulate this molecule and curtail inflammatory destruction in gum disease.
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