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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR039799-03
Application #
3160018
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1991-09-30
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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