Cytokines are important regulators and amplifiers of inflammation and immunity, They are produced by antigen presenting cells (APC) and lymphocytes during cell-cell interactions and in response to soluble stimuli. This study will consider four cytokines which may contribute to T cell function and to inflammation during immune responses in reheumatoid arthritis (RA): interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF) and interferon alpha (IFN-alpha. Freshly isolated APC like monocytes and dendritic cells (DC) will be compared in their ability to synthesize cytokines and factors controlling their production will be identified. Monocytes seem to differ from DC in their capacity to synthesize cytokines in response to pro-inflammatory stimuli. IL-1 and IL-6 are abundant in lipopolysaccharide (LPS) stimulated monocytes but not DC. Soluble stimuli like IFMs, lectins, PMA, mychobacteria and viruses will be tested for the production of other cytokines. Cytokines will be identified by single cell immunolabeling, bioassays, immunoblotting and in situ hybridization. The importance of the T-APC interaction in inducing cytokines in AFC will be identified. Alloreactive T lymphoblasts and T cell clones have been found to induce IL-1 in HLA-matched monocytes but not IL-6. DC fail to make either cytokine when subject to the same stimuli. Other cytokines induced under these conditions will be identified. The role of soluble inducing factors and function of cytokines in T cell activation will be identified. These studies will be extended to the rheumatoid synovial lining and synovial effusions. Synovial fluid appears to be rich in IL-6 but not IL- 1. The primary cells synthesizing relevant cytokines like IL-6 will be identified by approaches outlined above. The levels of these cytokines will be related to the clinical course in patients with RA and different types of arthritis. The data gained from these studies will provide insights into the function of APC and the role of cytokines in human T cell activation and conditions of chronic inflammation in vivo
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