Rheumatoid arthritis is an autoimmune disease with tissue manifestations predominantly in joints and systemic changes including hypergammaglobulinemia and elevated levels of acute phase proteins, Neuropeptides and cytokines as pathogenetic mediators in RA were subject of our previous work and represent the central theme of the present proposal. Our studies on interleukin-6 (IL-6) showed that it is a costimulant for the proliferation of T-lymphocytes, a differentiation factor for T-suppressor cells which it stimulates to produce increased levels of transforming growth factor beta (TGF-beta). We have identified multiple cell sources of IL-6, in particular, synoviocytes and chondrocytes, hepatocytes and endothelial cells. High levels of IL-6 are found in synovial fluids and this is likely to contribute to the elevated acute phase proteins and hypergammaglobulinemia in RA. Recently, we have begun to define the role of IL-6 in connective tissue metabolism and shown that in contrast to the other momokines IL-1 and TNF, IL-6 does not induce the production of proteases, but stimulates the production of the tissue inhibitor of metalloproteases (TIMP). In its effects on human articular chondrocytes and on Swarm rat chondrosarcoma cells we have demonstrated that IL-6 stimulates cellular proliferation and in this function expresses a unique synergy with TGF-beta. Biochemically, IL-6 represents a heterogeneous group of glycoproteins and we have observed the production of a larger 67 kDa molecule by hepatoma cells. Our studies on neuropeptides analyzed the role of neural factors in inflammation. We showed that substance P may directly contribute to connective tissue destruction by inducing the release of PGE2 and collagenase from synoviocytes. Subsequently, a pathway for nervous system regulation of host defense responses was identified by the demonstration that SP can stimulate the production of the proinflammatory cytokines IL-1, TNF and IL-6. This proposal is based on these preliminary studies and concerns (i) the characterization of 45 and 67 kDa isoforms of IL-6 which will be purified to determine their molecular nature and biological properties (ii) the effects of IL-6 on articular connective tissue metabolism where the effects on chondrocyte proliferation and chondrocyte secretory function will be defined (iii) studies on neuropeptides and joint tissue cells in chronic inflammation. Detailed analysis of SP receptor expression by cells from RA joint tissues is necessary to understand its role in RA. As a new aspect of neuroimmune interactions we will study the production of specific neuropeptides by cells of the immune system. From these studies we expect new insight into the pathogenesis of arthritis and other inflammatory diseases and this may provide the basis for new therapeutic interventions.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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General Medicine A Subcommittee 2 (GMA)
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
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Komuro, H; Olee, T; Kuhn, K et al. (2001) The osteoprotegerin/receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand system in cartilage. Arthritis Rheum 44:2768-76
Lotz, M (2001) Cytokines in cartilage injury and repair. Clin Orthop Relat Res :S108-15
Alaaeddine, N; Olee, T; Hashimoto, S et al. (2001) Production of the chemokine RANTES by articular chondrocytes and role in cartilage degradation. Arthritis Rheum 44:1633-43
Olee, T; Hashimoto, S; Quach, J et al. (1999) IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. J Immunol 162:1096-100
Rosen, F; McCabe, G; Quach, J et al. (1997) Differential effects of aging on human chondrocyte responses to transforming growth factor beta: increased pyrophosphate production and decreased cell proliferation. Arthritis Rheum 40:1275-81
von Kempis, J; Schwarz, H; Lotz, M (1997) Differentiation-dependent and stimulus-specific expression of ILA, the human 4-1BB-homologue, in cells of mesenchymal origin. Osteoarthritis Cartilage 5:394-406
Zvaifler, N J; Tsai, V; Alsalameh, S et al. (1997) Pannocytes: distinctive cells found in rheumatoid arthritis articular cartilage erosions. Am J Pathol 150:1125-38
Maier, R; Wisniewski, H G; Vilcek, J et al. (1996) TSG-6 expression in human articular chondrocytes. Possible implications in joint inflammation and cartilage degradation. Arthritis Rheum 39:552-9
Schwarz, H; Blanco, F J; von Kempis, J et al. (1996) ILA, a member of the human nerve growth factor/tumor necrosis factor receptor family, regulates T-lymphocyte proliferation and survival. Blood 87:2839-45
Lotz, M; Rosen, F; McCabe, G et al. (1995) Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes. Proc Natl Acad Sci U S A 92:10364-8

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