The long-term objective of my laboratory is to examine the possible role of monocytes and macrophages in human inflammatory diseases such as rheumatoid arthritis. The possibility exists that in inflammatory diseases where interleukin 1 (IL 1) may mediate tissue destruction, local IL 1 production by macrophages may be excessive. This unregulated IL 1 production may result primarily from the effects of differentiating or activating agents acting on tissue macrophages. The hypothesis to be examined in these proposed studies is that monocytes exposed to soluble differentiating agents, or cultured on particular substrates, will evolve into macrophages that exhibit increased levels of IL 1 production in response to triggering stimuli. These studies will examine IL 1 production in human monocytes, in vitro-derived macrophages, alveolar and synovial macrophages, and the effects of various physiologic agents or conditions that the cells might encounter in the rheumatoid joint. The proposed studies will be pursued under three specific aims: 1. To examine the mechanisms of regulation of IL-1beta production by human monocytes and in in vitro-derived macrophages in response to different triggering agents than LPS, such as PMA, silica particles, TNFalpha and a specific IL 1-inducing lymphokine. 2. To examine the mechanisms of effects on IL-1beta production by human monocytes of culture in differentiating agents such as IFN- gamma,1,25(OH)2-vitamin D3, GM-CSF or IL 4, and of culture on different substrates. 3. To examine regulation of IL-1beta production in alveolar and synovial macrophages and in cloned cell line derived from rheumatoid synovium. Monocytes and macrophages cultured in the presence of the various differentiating and triggering agents will be examined for effects on regulation of IL 1 production. The levels of regulation to be studied include transcription, translation and protein processing and secretion. These studies have direct relevance to the pathophysiology of inflammatory joint diseases such as rheumatoid arthritis where IL 1 may play an important role in the initiation of early changes in the joint as well as in mediation of tissue destruction. A greater understanding of the regulation of cytokine production may permit the development of more specific therapeutic agents in these disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR039950-03
Application #
3160193
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1990-08-31
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1994-07-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Malyak, M; Guthridge, J M; Hance, K R et al. (1998) Characterization of a low molecular weight isoform of IL-1 receptor antagonist. J Immunol 161:1997-2003
Malyak, M; Smith Jr, M F; Abel, A A et al. (1998) The differential production of three forms of IL-1 receptor antagonist by human neutrophils and monocytes. J Immunol 161:2004-10
Jenkins, J K; Malyak, M; Arend, W P (1994) The effects of interleukin-10 on interleukin-1 receptor antagonist and interleukin-1 beta production in human monocytes and neutrophils. Lymphokine Cytokine Res 13:47-54
Voelkel, N F; Tuder, R M; Bridges, J et al. (1994) Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am J Respir Cell Mol Biol 11:664-75
Malyak, M; Smith Jr, M F; Abel, A A et al. (1994) Peripheral blood neutrophil production of interleukin-1 receptor antagonist and interleukin-1 beta. J Clin Immunol 14:20-30
Firestein, G S; Boyle, D L; Yu, C et al. (1994) Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum 37:644-52
Arend, W P; Malyak, M; Smith Jr, M F et al. (1994) Binding of IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist by soluble IL-1 receptors and levels of soluble IL-1 receptors in synovial fluids. J Immunol 153:4766-74
Malyak, M; Swaney, R E; Arend, W P (1993) Levels of synovial fluid interleukin-1 receptor antagonist in rheumatoid arthritis and other arthropathies. Potential contribution from synovial fluid neutrophils. Arthritis Rheum 36:781-9
Jenkins, J K; Arend, W P (1993) Interleukin 1 receptor antagonist production in human monocytes is induced by IL-1 alpha, IL-3, IL-4 and GM-CSF. Cytokine 5:407-15
Patterson, D; Jones, C; Hart, I et al. (1993) The human interleukin-1 receptor antagonist (IL1RN) gene is located in the chromosome 2q14 region. Genomics 15:173-6

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