Rheumatoid arthritis is generally considered to be a chronic inflammatory autoimmune disorder that causes the body's immune system to attack its own joints. RA can result in loss of mobility due to pain and joint destruction. Although the cause of RA is unknown, macrophages and their products appear to play a key role in RA pathology. Monocytes in peripheral blood differentiate into synovial-tissue macrophages which produce numerous inflammatory mediators such as cytokines, growth factors, chemokines and proteases. Macrophages also express adhesion molecules, chemokine receptors and surface antigens that allow the macrophages to interact with other cells and ECM molecules. It is also important to recognize that macrophages may differentiate into osteoclasts, which further to joint destruction.
Factors such as Mcl-1 (an antiapoptotic factor) found on the surface of macrophages appear to have increased expression in RA macrophages. Increased expression of Mcl-1 would cause a resistance to apoptosis in synovial tissuse, which plays a role in the persistence of RA since the affected tissue is unable to self-destruct and make way for new, healthy tissue.
Products secreted by synovial tissue macrophages also contribute to RA. Interleukin-1 (IL-1) and TNF-a are the main proinflammatory cytokines secreted. TNF-a also stimulates the production of IL-6, IL-8/CXCL8, ENA-78/CXCL5, MCP-1/CCL2 and MIP-1a/CCL3, which are all secreted by macrophages.
IL-10, another synoival tissue macrophage secretory product, is normally thought of as an anti0inflammatory cytokine, however, this is not true for RA. It has recently been found that IL-10 induces TNF-a receptor expression on monocytes. Also, when IL-10 was stimulated, the expression of interferon-gamma-inducible genes was increased . Interferon-gamma-inducible proteins have been shown to have proinflammatory but antiangiogenic effects in RA.
Macrophage migration-inhibatory factor (MIF) is another cytokine produced by synovial tissue macrophage. MIF is shown to stimulate TNF-a, IL-1, IL-6, IL-8 and MMP production. MIF exresssion in RA is stimulated by glucocorticoids, which means that the antiinflammatory effects of glucocorticoids are overridden by MIF. MIF seems to be the most interesting and promising recently researched cytokine due to the many effects produced by the molecule.
There are numerous other factors expressed on the surface of or secreted by synovial tissue macrophages in addition to the examples described above. Therefore targeting macrophages and their products may be the key to treating RA.
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I thought it was helpful that we were tested on Tumor Necrosis Factor-A (TNF-a) the week before in biochemistry (for those who are in the class). It was nice to learn about a specific type of ligand and receptor in one class, and immediately be able to apply the new knowledge directly to another class.
It seems that a signaling pathway linking Glucocorticoids and MIF needs to be mastered and then an inhibitory drug for administered for MIF activation along with prednisone could be a valuable treatment
MIF is old: one of the first cytokine activities to be identified, and is usually secreted in higher levels by fibroblasts and epithelial cells than macrophages/monocytes themselves. (Hagemann, et. al., Mol. Cancer. Therapy, 2007). MIF binds to CD74, a component of MHC II invariant chain, and although it clearly has effects in MHC II negative cells (non APC) it's receptor has not been ID'd. ISO-1 at about 100uM can reduce MIF activity nearly as well as sRNA (Rendon, et. al. JBC 2007). IL-10 when co-administered with LPS dramatically decreased all cytokines assayed (Stout, et. al., J. Immunol., 2005), thus getting back to the specific activation state of the macs, and that the response to a stimulus has to take into consideration other concomittant stimuli. MIF is even more complex, because it appears to have completely different functions in every cell type; i.e. increased RAC1 and ERK activity in epithelial cells, leading to increased mobility (and growth), yet increased RhoA activity in fibroblasts, leading to decreased mobility.
Your observations about macrophage mediated joint destruction are very astute. These phenomena are very significant in the later stages of RA and likely play a key role in the pathology of the disease, as you noted. Do you think that the regulation of this downstream disease-linked process might be affected by upstream induction methods eg. difference between complement dependent c5a chemotaxis vs DAMP mediated macrophage attraction? Could different types of macrophages (maybe expressing different cytokines and membrane receptors) be attracted based on the type of induction?
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