The inflammatory cytokine, TNF alpha, has been shown to play an important role in rheumatoid arthritis (RA) through the study of murine collagen induced arthritis (CIA). These results have propelled several TNF alpha blocking drugs into clinical use. These drugs are not universally effective and can have serious side effects. Importantly, the role of TNF alpha in RA is not fully understood. Blockade of TNF alpha signaling, both in CIA and in RA, does not stop the disease but rather slows disease progression. In the CIA model, signaling through the p55 TNF receptor (TNFRI) has been shown to mediate some TNF alpha effects however signal transduction through TNFRII has not yet been investigated. In addition, TNFRI signaling is complex. Through interactions with the adapter protein TRADD, TNFRI can activate both FADD and caspase mediated apoptosis as well as TRAF2 and RIP, leading to activation of JNK and proliferation as well as NF-KB mediated antiapoptotic and proinflammatory responses. Through interactions with the adapter protein FAN, TNFRI can activate neutral sphingomyelinase and the production of ceramide, which in turn activates a variety of signaling events. The relative importance of these signal transduction cascades for arthritis is currently unknown. TNFRI and TNFRII are present on multiple cell types. Thus it is likely that different cell types may favor different signaling pathways when activated by TNF alpha. We propose to identify specific subsets of tissues in which TNF alpha signaling contributes to the development of arthritis in the CIA system. Our strategy is to use bone marrow (BM) transplant technology to place TNFRI-'- BM into irradiated TNFR+/+ recipients or conversely, TNFRI+/+ BM into TNFRI -/- recipients. Similar experiments will be performed with TNFRII mice. By this means we can distinguish between the contribution of hematopoietic TNF alpha signaling versus non-hematopoietic TNF alpha signaling to CIA as well as the relative importance of TNFRI and TNFRII signaling in this process. We will then begin to dissect the signal transduction cascades mediated by TNF alpha activation of TNFRI by introducing dominant negative adapter proteins using either retroviral mediated gene transfer into hematopoietic BM stem cells or by creating transgenic mice delivering the dominant negative proteins to the synovium. In summary, these experiments will increase our understanding of how TNF alpha signaling in different cell types contributes to CIA.. By extension, these data will help us understand more fully the mechanisms of action of TNF alpha blocking drugs and potentially will identify new targets for future arthritis therapies.
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